肝癌药物研发状况与市场分析
肝癌药物研发状况与市场分析肝癌是临床上最常见的恶性肿瘤之一,恶性程度高,病情发展快。全球肝癌发生率较高的国家集中在亚洲、非洲。从目前全球药物研发状况来看,肝癌药物明显少于乳腺癌和肺癌等。由于中国是肝癌的高发区,肝癌药物的研发在我国愈来愈受到重视。本文以IMS R&D Focus 作为数据源,利用TDA 的分析功能及文献调研等方法对肝癌的发病率、全球肝癌药物的研发状况以及肝癌药物的市场情况进行了介绍,以期对我国肝癌药物的研发起到些许借鉴作用。
1.肝癌发病率
根据美国癌症协会公布的调查结果得知,在全世界癌症发生率前14 名当中,肝癌位居第6 名,每年全球新增71 万名肝癌病患。据NCI 公布,2013 年美国肝细胞癌和肝内胆管细胞癌的预计新病例为30,640 人,死亡病例为21,670 人。据英国癌症研究院公公布,英国2010 年4241 人被诊断肝癌,3789 人死于肝癌。而全球肝癌发生率较高的国家集中在亚洲、非洲,其次是中非国家与日本,中国位居全球肝癌发生率的首位,世界上超过50%的肝癌病例发生在中国,目前我国每年发病人数约34.7万,约占全球总发病人数的55%;死亡人数约32.3 万/年,约占全球总死亡人数的45%,在肿瘤相关死亡中仅次于肺癌,位居第二。
2.肝癌药物研发现状
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Xdc+cefYhh0puX1qxu/liZuJQRazDF58fEn3rxNP+nAJA2NSnjum5/f7/YIxNIGbkJfKZpBhZpwrngR4Nt2/l8Xn6wWCxevnx5bGws8OGB14xc0TEMIxAx/m8hkDLPPfecWKcJ/I7kkGpAZMpMPvwgw6Q3gY5RmzLep8swuRUDf7m/zGG/ADRTmTIiEeRv/KIPDhw4EAiUcrkcOBglbvEmkBFxmkkZy7LCCeUv28zMzMzMzKSaMlfOTU08cC/DpDfhlGngujIJKeN9ujYjpnz8vcb+dABAA9JdlRGrL67rXrlyJfkVElIm3ChhaazKyDuYUk2Zy1NTR+7dwDDpTaop4x8XXPngoutW+594Wd7fBABpSzFl/HOCxK+KA1biXiEhZWrpBiUpI96kL+FYmchXqFE4ZRamzv7vDesZJr1JL2VEu0Qe9hu3fgMAaqWYMrt27ZIzQgRBsViM/LdaXSljGEbgdTK9KvN/z575n19YyzDpTThlGvjSjUyZwEVl5GeyMANAj7RS5tixY+E1GNM041JGnOG8cePGyMNWAiqVim3btm3LH57dlJk7c8ZcexvDpDfP3rgqpZSJrJbko2oAQK20UubixYue583NzUU+/8KFCwsLC/Ijcasvg4ODhUJh7969yResS3sHU6op43nea323MEx6s2NVb/P3kky4rkzgUN/wlWYAID3pHvYrLo4XKRAZ4TOVRDHMzMwUCoWFhQX5Urxhqa7KWJYlLyalkTJvPLH1hdU3MkxK853rexpekhG7kPyzkyJPU/JPxuYeTAD0Sz1l/LyQfxy+2Ezgirr+C/rdIH94WEops2fPnmq1Gj5bW+1hv57n/dVXH/92TzfDpDTNL8kAQNtql5QJXDTPf4KfMsm3C2gmZcKXBpYVi8XR0dHAjQuUr8rMTJz4r5/5DMOkN3+4sqvho2QAoJ21S8oYhuEfDSPv0JG7Qb4vUkDzqzKedEfJwF0U5PfmpZMynuftf/GFhPnGpvu/sen+5OcwTPKM737FPnWysa9bAGhbbZEy8o2WHMfp6+vzQyHQDXF3plSSMmJ5RryI/w4D7yf8luoVlzIJZmdnS6XSyMhIY58RAIBlTFnK+C3SQMrYti3upF1LN/iHEgdWSppMmcAn8uMsvIBEygAA0D7U3xlb3j1UY8qI+zEteRNs+fnDw8Pj4+NiZ1Dzd8aOvEBfuVyOPHOKlAEAoH2kkjJ+JcgnYwdiwk8Z13UPHz4cOIHI12Q31CIyobzQEpHjOP4NupWfwZSMlAEAIE7qKRN5BvWhQ4f8apmcnIw7L8lLP2XiEiphP1TCiVS1IGUAAFBIfcogGSkDAIBCpIxupAwAAAqRMrqRMgAAKETK6EbKAACgECmjGykDAIBCpIxupAwAAAqRMrqRMgAAKETK6EbKAACgECmjGykDAIBCpIxupAwAAAqRMrqRMgAAKETK6EbKAACgECmjGykDAIBCpIxupAwAAAqRMrqRMgAAKETKpK4UhZQBAEAJUiZ1pAwAAOkhZXRjBxMAAAqRMrqRMgAAKETK6EbKAACgECmjGykDAIBCpIxupAwAAAqRMrqRMgAAKETK6EbKAACgECmjW3LKvPnfvhE5L9yz4YV7NsT9KsMwDMM0PHu/vuW1wcftUyc1f0NUhZTRLSFl3h3ZY669g2EYhmG0zWt9t2zv6d7e0/3a4OP6vycqQcroFpcy9r69b21YzzAMwzA6Z+fNN4qU2d7TndGFGVJGt7iUOf/6/n+5726GYRiG0TY/uu1zfsdkd2GGlNEtLmVOPnAvwzAMw+ickdtvJWVQt8iUuTj2+pkv3c8wDMMwOkfuGDGt+ubYDFJGt8iUmXtzbPrhBxmGYRhG55Ay0SzL6urqqlar8iPlcrmBl7Jtu6Ojo1KpqHt3sRzH2blz5+LiovipaZopfd7IlDn/3Wd+/uhDDMMwDKNt3lh3Ry0pY+zYn1sx0LnmqflLH/3a982rH+e7tuZWDIgpH38vjW+atUglZQYHB0dHR/1HDMPI5XKN1YxlWZ2dnfPz8+reYDTHcfL5/PDwsPipaZr+57Usy3/c8zzbtleuXNnwW4pMmV889gjDMAzD6Jw31q9dMmXs83Md120Jp4x1+v3cioHhfeXIn2qmPmVs2x4aGvKXNxzH6e3tXfIbv23bR48eDT/uum6pVJLXeMSTC4VC4EHP8yzLykmKxeLi4qIIKV9cUbmuu23bNv99mqbp54tYHJJfpLOzc3p6eqktES0yZd599CGGYRiG0TnmujuTU8Z1q/1PvFx8fuyb39krp4x4vGvd9mr1E//Jxo794ZUbPdSkjOu6/f39Yo9MIGXkJvCZphlIinAu+NFg23Y+nw80yuXLl8fGxiLfjLygIgRWXOJ+C4GUee6558RHBX5HcSFVo3DKXH333NTmfoZhGIbROX+xZnVyylin3xd1EsgUsWspsAYjFmYqH1xs7JtjM1SmjDhERv7GL/rgwIEDgUApl8uBg1HiFm8CGVGLelMmsJbjE7+dmZmZmZmZVFPGOTf9r/2bGIZhGEbnvFi4OdAx8snYcq8EUkbsdYpMmZYcMZPuqoxYfXFd98qVK8mvkJAyHR0ddR1no2pVRt7BlGrKXJmeOnbf3QzDMAyjc/589U0JKWMenPB3IUWuyhSfH5MXGiL7Ro8UU8Y/J0j8ai6XSzgnKCFl6u2GhlNGvElfwrEygVO06hJOmf+YOvtP93yRYRiGYXTO96VbFogZ3/3Kf37jOz/Xcd0Wf4klfByMeXBCXoMRR8+06sjfFFNm165dck+IIBCH4oZfoa6UMQwj7nW8DK7KXDo7+bO71jEMwzCMzvneTTfEpYyxY7+86BJ5SK+oGTGda56aOPNvcv3olFbKHDt2LLwGY5pmXIKIM5w3btwYedhKQKVSsW3btu3IN5O5lJmfPPM36+5gGIZhGJ0zdOOqyGN+wwfw1nJ20jI57FdOmYsXL3qeNzc3F/n8CxcuLCwsyI/Erb4MDg4WCoW9e/fWfsG6NHYwpZoyF8+8s+e2zzEMwzCMzvnuDddHHigjL7cEJnAC9q998z04sTxPxg5c00UWqI3wmUqiGGZmZgqFwsLCgnwp3mTKV2Usy5IXk5SnjOd5/+OzqxmGYRhG53zvplWRe5fCllyViTw9W5vUU8Y/+Uj+cfhiM4Er6vov6HeD/OHJFKbMnj17qtVq+GxttYf9ep73ky1f3bGql2EYhmG0zXdW9dR496XklIk8oUmndkmZwEXz/Cf4KVP77QLqTRnTNBOOyykWi6Ojo4EbFyhflXl/YuIPfvd3GIZhGEbn/HF315JLMl5UyogbM7XDDZi89kkZwzD8o2HkHTpyN4QbJVJjqzKedEfJwF0U5PfmpZMynue98Rc/2PQbnQzDMAyjbb78W/9le0/3q4Nfaew7Wptoi5SRb7TkOE5fX58fCoFuqOXOlA2njFieES/uv8PA+wm/pXrFpUyC2dnZUqk0MjLS2GcEAGAZU5Yyfos0kDK2bYs7adfSDf6hxHHnNDWWMoFP5MdZeAGJlAEAoH2ovzO2vHuoxpQR92Oq/SbY4sPHx8cDRxg1fGfsyAv0lcvlyDOnSBkAANpHKinjn+AjZ4RY4QhftcV13cOHDwdOIPI12Q21iEwoL7REJJZ2UjqDKRkpAwBAnNRTJnIV5NChQ361TE5OJhzJm3bKxCWUYRiRvVL7iVRxSBkAABRSnzJIRsoAAKAQKaMbKQMAgEKkjG6kDAAACpEyupEyAAAoRMroRsoAAKAQKaMbKQMAgEKkjG6kDAAACpEyupEyAAAoRMroRsoAAKAQKaMbKQMAgEKkjG6kDAAACpEyupEyAAAoRMroRsoAAKAQKaMbKQMAgEKkjG6kDAAACpEyqStFIWUAAFCClEkdKQMAQHpIGd3YwQQAgEKkjG6kDAAACpEyupEyAAAoRMroRsoAAKAQKaMbKQMAgEKkjG6kDAAACpEyupEyAAAoRMrolpwy/376dHj+5e/+9lnjv+/7wQ8if5VJng9OndL8vxgAoBMpo1tCypzd8+M9t/UxCuf7q2/a3tO9vafbPnVS//9rAIAGpIxuCSlz6IufZ9SO6JjtPd2vDT6u//81AEADUka3uJSZfX1feeNdjML5q1tv8VNme093S/53AwDSRsroFpcyJzZtZNSO3DHsYwKA5YqU0S0yZT46N3X6wfsYhfO/NnyBlAGAawEpo1tkyvxqzDz70AOMwhlde3sgZcZ3v9Kq/+kAgPSQMrpFpsz834y9u7mfUTgvrSmQMgBwLVCfMpZldXV1VatV+ZFyudzAS9m23dHRUalU1L27WI7j7Ny5c3FxUfzUNM2UPm9kyvzisUcYtRPomAZSxjr9fm7FwPC+iC9d1632P/FybsWAmMjnAAD0SCVlBgcHR0dH/UcMw8jlco3VjGVZnZ2d8/Pz6t5gNMdx8vn88PCw+Klpmv7ntSzLf9zzPNu2V65c2fBbikyZn3/5YUbtNJkyxo79cZniXP0437W1+PyYCF/7/FzHdVv8nwIANFOfMrZtDw0N+X+tO47T29u75Dd+27aPHj0aftx13VKpJK/xiCcXCoXAg4EndHR05D5VSwy5rrtt2zb/aaZp+vkSeDXxgtPT08kvGCecMlffPXducz+jcN6+7+6GU0aUSm7FwOnpD/NdW8MpYx6c6Fzz1Pylj+RHcisGKh9cbOxLAgDQDDUp47puf3+/2CMTSBm5CXymaQYWacK54EeDbdv5fF5+sFgsXr58eWxsLPldWZaVy+Vq3E8UTpnnnntOrNMEfkdLhlSycMo4755756EHGIXz1j1fbDhl7PNzhft3VKufiKYJpExgScb/kI7rtrCbCQBaQmXKiENk5G/8og8OHDgQCJRyuRw4GCVu8SaQEXWpMWXE08LEb2dmZmZmZibVlLkyPWU9cC+jcP7+i+vCKVPvydiRKRNZLZF9AwDQI91VGbH64rrulStXkl8hIWU6OjoaPs6mmVUZeQdTqilzeers4Xs3MArnwPo7wylT7/+phJQpH38v/ExSBgBaIsWU8c8JEr+aXBUJKdNwN9SbMuJN+hKOlQmcolWXcMosnJ18a8N6RuGYa28jZQDgGpFiyuzatUtOExEExWIx8q/7ulLGMIy415FlZVVm/uyZA+vvZBTOT27va/6iMuxgAoBMSCtljh07Fm4I0zTjEkSc4bxx48bIw1YCKpWKbdu2bSe/q6ykzK/OnNl/x62Mwnm1b43+lOGwXwBoibRS5uLFi57nzc3NRT7/woULCwsL8iNxqy+Dg4OFQmHv3r0NXLBO4Q6mVFPG87zhWz7LqJ0m9y55MYGScAZTYK8TAECPdA/7FRfHixS41kv4TCVRDDMzM4VCYWFhQb4Ub41UrcpYliUvJqWRMqNbtzx/0w2MwvmT63uavGVB3FqLsWN/+LoygUcAANqknjL+yUfyj8MXmwlcUdd/Qb8b5A+vUfMps2fPnmq1Gj5bW+1hv57n2adOfqu7i1E4f9zdlVLKBC7vy0VlAKC12iVlAhfN85/gp0wDtwuoMWVM00w4LqdYLI6OjgZuXKB8VcbzvEd/67cYtdNYx4g08e+v5I+8/8i/IrAYrvMLAC3ULiljGIbfHPIOHbkb5Psi1aKuVRlPuqNk4C4K8nvzUksZz/Omjh+PnIOjo9964olXnn8+7glM3NR7WTwAQOa0RcrIN1pyHKevr88PhUA31HVnynpTRizPiBf332Hg/YTfUr0SUibO7OxsqVQaGRlp7DMCALCMKUsZv0UaSBnbtsWdtGvpBv9Q4hrvSFBjygQ+kR9n4QUkUgYAgPah/s7Y8u6hGlNG3I+p9ptgiw8fHx+PO6ep3jtjR16gr1wuR545RcoAANA+UkkZ/wQf+WRsscIRvmqL67qHDx8OnEDka7IbahGZUF5oichxHP8G3crPYEpGygAAECf1lIk8ruXQoUN+tUxOTiYsmaSdMnEJZRhGZK80cCJVACkDAIBC6lMGyUgZAAAUIiGta9MAABEkSURBVGV0I2UAAFCIlNGNlAEAQCFSRjdSBgAAhUgZ3UgZAAAUImV0I2UAAFCIlNGNlAEAQCFSRjdSBgAAhUgZ3UgZAAAUImV0I2UAAFCIlNGNlAEAQCFSRjdSBgAAhUgZ3UgZAAAUImV0I2UAAFCIlEldKQopAwCAEqRM6kgZAADSQ8roxg4mAAAUImV0I2UAAFCIlNGNlAEAQCFSRjdSBgAAhUgZ3UgZAAAUImV0I2UAAFCIlNGNlAEAQCFSRjdSBgAAhUgZ3RJS5uLkmYPf/P1dt3yWYRimrnn2xlXbe7rf/uFu/X+nAS1HyuiWkDJHv/WHf7vuToZhmLpm15rC9p5uMfr/TgNajpTRLS5lPti/b/zuLzAMw9Q7fsds7+m2T51syd9sQAuRMrrFpcz008Vj99/DMAxT1/z49j45ZV4bfLwlf7MBLUTK6BaXMqceuJdhGKbeGbnjVlIG1zhSRrfIlLk4Zk72b2IYhql35I4hZXBtImV0i0yZ+TfHzj38JYZhmLrmn+7dEEgZjvzFNai9UsayrK6urmq1Kj9SLpcbeCnbtjs6OiqVSl0fMjQ0tLi4KD/oOE5vb+/8/HwD7yFSZMr8e+mZmS8/zDAMU9e8sf7OxlLG2LE/t2LAn8oHF+t9AtA+2i5lBgcHR0dH/UcMw8jlco3VjGVZnZ2ddVWIZVm5XE4OINM0Ozs733rrrQbeQKTIlJl57BGGYZh65431axtIGfPgxPC+//xL1XWr/U+8HIgV8+BE8fkx8e+6yCcAbaW9UiawLlLjioht20ePHg0/7rpuqVSS13jEkwuFQuBBmWEYxWJRvAfHcXbu3BlYp2lSZMqce/QhhmGYeuelNaub38Fkn5/ruG6LHzdxT/DjBmg3rU8Z13X7+/vFQkggZUzTHB4eDjzfNM3AIo3Yl5QL6ezstG07n8/LDxaLxcuXL4+NjcW9nwsXLiwsLIgf79mzJxA9pmk2vEokhFPm6rvnJh9+kGEYpt75wWeDKdPAYb/O1Y/zXVsTUkY8gZRB22qXlBGHyMgp47rutm3bDhw4EAiUcrlsmqa8Dyhu8Sby2BeZ4ziB0Mnlck8++eSmTZvEj0+fPh14goiYQ4cONXz0TDhlPjo3dfLB+xiGYeqdFws3NZ8y1un3cysGysffi/2rkpRBe2uXlAmvyojVF9d1r1y5kvwKCSnT0dHRzApK4LOcOHGi+dcJp8zlqal/uXcDwzBMvfPnq4MpM777lbr+RhI7j7rWba9WP4l7zpKtA7RWm6aMf5CK+NXAobgBCSmTfFiMzzCMwKG+4R1bYgnHP4ymYeGUWZg62/ILnzMMk8XZefONjaWMeXDCPzspuWPEkkzyc4DWatOU2bVrl5wmYn0lLiPqShn5qF6fOAJGNjQ0JD7QNE2x80vVWdnhlLl09szff2EtwzBMvfO9m1YFUqaBezCJ867jjpURv8rpS2hn7Zgyx44dC6/BmKYZlzK2ba9cuXLjxo3hI3/DKpWKbdu2bQdeXN4PJf/U/3F6KTM3eWZs7W0MwzD1zrM3BlOmsb+X4npFPM6uJbS5dkyZixcvep43NzcX+Xz5DCMhbvVlcHCwUCjs3bt3yQvltTZlPM/761tvYRiGqXd23HB9MwfK/P+/9A5OhFNGPJhwZhPQJtoxZcTSi7g4XqTAhe/CZyqJuJmZmSkUCgsLC0teGya8g0lzyrz5xDd+sPomhmGYuiZwrEzDKWPs2N+55qn5Sx/5j4hDfekYZEJbp4zfE/KPw8fkWpYlP+K/oL9aI394pJavyvzoq1/9094ehmGYuubp3t+rd++SOIxX3mcUrhbxCGdfIyuWQ8qEQ0Q8wU8ZcTBNQoW0PGV+MTGx5brfZhiGqXf+qLur3iUZcQJ23C2W/DsVhIeDZtCelkPKyKdSW5blHx0sH0MjbqUUFyIt38Hked7rL7747f7+uHls9erHVq9OeALDMNfmPLt584sDjzW8awlYBjKfMvKNlhzH6evr84//DRwOnHBnypavyiSbnZ0tlUojIyNNfmoAAJaftkgZv0UaSBnbtsWdtAMd40Wd2eQfShw4pykhZQzDEJ+OlAEAoA21PmVk8u6hGlNG3I+p9ptgiw8fHx+XD2dLSBkfKQMAQBtqu5QRl9b1fv1k7EqlIh/O4qeM67qHDx8WN55s5sYFfrv4n9RPGfm22/57awYpAwCAQm2dMpHHtch3pZ6cnExYJqnrHkxyu4Q/SgTNkpfaqwUpAwCAQu2VMtcCUgYAAIVIGd1IGQAAFCJldCNlAABQiJTRjZQBAEAhUkY3UgYAAIVIGd1IGQAAFCJldCNlAABQiJTRjZQBAEAhUkY3UgYAAIVIGd1IGQAAFCJldCNlAABQiJTRjZQBAEAhUkY3UgYAAIVIGd1IGQAAFCJlUleKQsoAAKAEKZM6UgYAgPSQMrqxgwkAAIVIGd1IGQAAFCJldCNlAABQiJTRjZQBAEAhUkY3UgYAAIVIGd1IGQAAFCJldCNlAABQiJTRjZQBAEAhUka35JT55TvvHH/t1cCMPv309wYeG3366fAvMc3PP//lD9/+4W7NXwYAAFVIGd0SUmb6Jz/ed+dtjM55sXDz9p7u7T3drw0+rv+LAQDQPFJGt7iUuXR28h/uWsdoHtExYlry9QAAaBIpo1tcysy+vu/wvRsYnfPXt90ip4x96mRLviQAAM0gZXSLS5mJTRsZzfNi4SY5ZcZ3v9KSLwkAQDNIGd0iU+bi2OvvfOl+RvPIHcPhMgCQUaSMbpEp86s335h66AFG54yuvZ2UAYBlYHmmjGEY5XJZ/Ng0zUql0tr3I4tMmdnvPvPe5n5G55ifv0NVylin38+tGBjeV274CQCAhi2TlHFdt1QqVatV8VPDMHK5nF8wgZ8mMAyjWCwuLi7u2rVrfn4+/Kt+ITUsMmV+8dgjjOZ5aU1BScoYO/bnVgwklMqSTwAANGOZpIxt2x0dHaJCXNft7+8PNIdpmuGaER+Vk1QqFdu2bdsW9RM2Ojq6uLjYzFuNTJmff/lhRvM0nzLO1Y/zXVtzKwZOT3+Y79oaLpUlnwAAaN4ySRnTNEXHeJ7nOE4+nw9Ui+ibuIUZx3H6+vr8RR1PWoCZnJz0l2cMw2h+X1U4Za6+e256cz+jeQId00DK2OfnCvfvqFY/EckSLpUlnwAAaN5ySJlAu9i2XSgU5C6p5RXiUsayrFwuJ36cUso456ZP929iNE84ZRo+GXvJUiFlACA9mU8ZsdziL8l4nmdZlvzTgMjjZpJTxn+1lFLmyvTU8U0bGc1DygDA8pD5lPE8z3Gc8fFx+aiXwcHBwEEw8tEwnudNT08HXqGFKfMfU2fLG+9iNA8pAwDLw3JImYDag0PsmQq0TldXV7Va1Zky3H2p5XdfavLGBaQMALTQcksZx3F6e3vD51FHntYkf5S/KuO67pUrV/yUMU1zeHhYPC2lk7HnJ8/87fo7Gc0TTpmG/5+SMgDQQsstZSzLevLJJzdt2hS5d0msuIQ/KmEHk4aUuXjmnZHb+hjNU7rhelU3YCJlAKCFllvK+LWxZ88eOU3ks7XDElLGMIyf/vSnJ06c8NK8RN7La1YzmufPVvWQMgCwDCyrlJH3Ltm2ffToUfG4bdsrV64M73WSPzAyZcQL2radz+fL5XJ6KbPv61979obrGZ3zzKpeJXuXPFIGAFpqWaWMvDPI+/Qo3eSjZIS4lBGXqFlYWIg8/qYxkSnz/skJY+XvMnqnq8klGfv8XMd1W8RNCeQpH3+vxicAAJq3fFImnCNiTeWFF15I2LUkf+yRI0fkE7a9T9socCjxhQsXFhYWGn6fkSnjed6fPfLIl37jNxid89Xf/kyTu5YAAC23fFImcu+PZVmdnZ3JCyrier65XE5e0fGk3VV6UibB7OxsqVQaGRlp+JMCALBcLZOUsSwrECKe55mm2dnZeeDAAf/OAwHidpKRpzXJu6UCKSPuN9nwWyVlAABQaDmkjG3bQ0ND8i4kESJ+3Ph3wF5yT5NPXuMJpIxlWc0c/EvKAACgUOZTxnGcnTt3yoFiGEbkTiV/R1LCBWa8qBtrhy8KvOROqwSkDAAACmU+Zfzrx4j7RIZvFRngum5cRojWSagcJUgZAAAUynzKZA4pAwCAQqSMbqQMAAAKkTK6kTIAAChEyuhWb8rMzs42UD8AAFwjSBnd6uoSsR4jlmRmZ2fTfm8AAGQOKaNb7Slz5MgR0TGsxwAAEIeU0a2WlPF3KpVKJRZjAABIQMrotmTKsFMJAIDakTK6JacMO5UAAKgLKaNbQsqwUwkAgHqRMrpFpgw7lQAAaAwpo1s4ZdipBABAw0gZ3QIp4+9UomMAAGgAKaObnzLsVAIAoHmkjG7+MgyLMQAANI+USV0p3sjIyGEAANpGq79nNoKUSV1cx3wX6rBJ1WJ7KscmVYvtqZy/ST/88MNWf9usGynTAv6uJajCJlWL7akcm1Qttqdymb6qGSnTAuIrptXvYllhk6rF9lSOTaoW21O5TG9SUqYFMv0V057YpGqxPZVjk6rF9lQu05uUlGmBTH/FtCc2qVpsT+XYpGqxPZXL9CYlZVog018x7YlNqhbbUzk2qVpsT+UyvUlJmRbI9FdMe2KTqsX2VI5NqhbbU7lMb1JSBgAAZBgpAwAAMoyUAQAAGUbKAACADCNlAABAhpEyAAAgw0gZAACQYaQMAADIMFIGAABkGCkDAAAyjJQBAAAZRsoAAIAMI2UAAECGkTL6uK7b39+f+9Tw8HCr31FWWZYVtwHZyHUxDCMnqVQqgSewPevFJk2P2LadnZ3z8/Py42zS2om/PAPK5bL8nCxuT1JGE8dx8vl8sVhcXFz0PM+27Y6ODv+nqJ3/rSL8B4yNXBfTNP2N4//lJX/rZXvWyzRN/8uSTaqW2FbhlGGT1kWkTKBdZBndnqSMJqZpBv4EmqYZ+Y82xBF/xnK53OnTp/P5fDhl2MjNCP+dxfZsktik8hcqm7QxoguLxeI3v/nN8AZkk9ZuyZTJ6PYkZXQIdK4Q/msOyWzbLhQK1WpVbM/ApmMjNymwAdmezQt8obJJG2ZZlvj+ahiG/I2WTVqv5JTJ7vYkZXSI/FKI/KJBLSJTho3cpMiFZbZnMwLfNtikjZH/vAdShk1ar+SUye72JGV0EF8fga+eTHx9tKeElGEjNyzy+y7bs2FiA3Z1dVWrVfkRNmm9TNP0N2NkyrBJaxc+7FfeetndnqSMDtn9+mhPpIxyYkPxfbd54sACQd6eHpu0IYGNRsqoJb5c/b9Ls7s9SRkdsrtq157YwaScOC9MPrKP7dk8sVUD3yfYpHUxDEPeOOxgUk7epNndnqSMDglfH21+LFV7qjdl2MjJxHfcwD/F2J5KyI3IJq2X2BsiF3btKcMmrZF8glJ2tycpo0PCYeEJJ8UhTr1nMLGREwRWmH1sTyXk7xNs0nrJe+sCxM47NmnzlseXKCmjSeAfE17U6fuoUdy/EtjI9Uq4brLH9lQhsA3ZpE0Kb0A2aTPEBXvkg7oyuj1JGU0C1x/LxJn6bSsuZdjIdREdk7ALnO1ZF/FlKf/jNVyKbNImhb/Rsklr5zhOb29vIAQjD5LL3PYkZfTxL1Ybd3MWJPOvXJ5wMiEbuUaB26ywPZUIf4mGtxibtBnhlPHYpPUI7LMLnGQnZHF7kjIAACDDSBkAAJBhpAwAAMgwUgYAAGQYKQMAADKMlAEAABlGygAAgAwjZQAAQIaRMgAAIMNIGQAAkGGkDAAAyDBSBgAAZBgpAwAAMoyUAQAAGUbKAACADCNlAABAhpEyAAAgw0gZAACQYaQMAADIMFIGAABkGCkDAAAyjJQBAAAZRsoAAIAM+393VQkpe4hHmwAAAABJRU5ErkJggg==
图1:肝癌药物各研发阶段的分布情况(不包括撤回药物)
据IMS 数据库统计(检索日期:2013 年6 月19 日),目前全球肝癌药物有149个,除了少部分撤回研究外,大部分肝癌药物处于临床前和临床各研究阶段。其中临床前的肝癌药物有32 个,临床3 个研究阶段的药物共有77 个,而目前上市的肝癌的药物只有5 个。(注:本文中各研发阶段是指该药物针对肝癌作为适应症的研发阶段,并非该药物的最高研发阶段。)
(1)肝癌上市药物
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zbt28b6994440h3QBic3Bw8Mwzz2xvb+/v73/77bcbGxtbW1vb29tbW1t4Ojdu3HjooYc8z7t27doHH3xgHL63t3fx4kX9NDc2Ni5durSzsyNrdnZ2PM974YUXujT6/fv3n3/++cuXL5dlaay3r0jWnL/85S+/+MUvNjY29vf3m6bxPK//3f/666+9AVy8eDEIAnYjCVkrIEvef/99/G2a5oknnnjnnXfen7G1tfXaa685j33xxRdv3br14MGDMAx3d3e7LvHRRx9tbGzQTLBujEvH7+/vX758+fr160EQBEGwtbXleR5+Y6VeEwTBjRs3wjC0TeZ4Yfb29oz1UHtzk/Hll19ub2//5Cc/sdvg//qv/3rttdco5Y/He++953mefgRffPHFpUuXwjB89913H3744c3NzY8//tiZvXt7exsbG8aaZ599VtdZRkVpcHh4ePPmzQsXLtiPdWtrK0mSt99+e0k3Ss4D29vbly5dunv3Lv4+99xzXUVLqOt67g7OqokQcr6xdfzFixdv3Lixt7e3t7d348aNLiPU/fv3r1279txzz7VKwxweHr7xxhtff/1127Z//etf33777f39fer49WRcOt7g8PDw8ccfv3nzpgi7MAyvXr367rvv9h/47bffHlvHHxwc7O7uPvbYY19++WWu+PLLL5977jnP83Z2dugse2x2dnY+++yztm3v37+Px/rtt99evHjx5z//+Z///Oe2bQ8PD8WZQXNyHf/uu+9evXr1lVdeyY8SRdG//du/PfLII1988cVyb5ZMl7t37166dEmbvu7cuXP9+vVjv/tocanjCVlPpHna39+Hk/DGxoZUBR999FFX4/WnP/0JI9UgDEP8eOaZZ37961/fv38fRnrq+LVljDr+4OBAuqQff/yx53l37txp2/bw8PDKlSuvvvoqmtIu5/i21x5vaEGDw8PD11577aGHHrp9+7Zx8j/84Q9PPvnkzs7Ose+LaPb29jY3N7e2tra2tn784x8/9NBD165d29raunz58qVLl37zm9/Y+59Ex3/99dc7OzsPP/ywUcc9ePBgd3f3woULYnYlpG3bnZ2dZ599VtvG6rq+fPnym2++6dz/m2++6Zm58frrr1+7du2rr76ijidkrbh79y4s7tDfQRBcvnz5ueee+/rrr4fo+MPDw6tXr96+fRtWJ3giiBGqKIpWGSip49eTMer4b775ZnNz89VXX0Xp/9GPfhSG4d7e3u7u7qOPPro3Y3Nz8/bt204302Pr+Hfffffxxx9/6aWXdnZ23nzzTXkf3nnnnc3NzStXrizrHteWr776Ch0k6PK6ruu6jqJIfidJsrGxcf/+feNA7L+nuH79+rPPPnvz5k1Zg4rSrgr39/eDILh69epzzz0Xx7H4z+zv79+6dcvzvPfee+8M7p1Mhc8///zChQsffvihsT6KomvXrsGybhCGofRLbTCL4+WXX/7++++p4wlZHw4PD6Mo+uijj6IogjX9o48++uijjzBJbK6O/9vf/ra5uSl/tU/B/v4+pnVRx685Y9TxUOFS3G/duvXee+99ZHH16tUbN244TfI4g5MeHf/2229fvnwZL1IYhk8++STesQ8++GB3d/fxxx//4YcfTu+uzzH7+/vQ2Tdv3nzsscfCMITzjDwL/burJsI+ugDcuHHj2WefjeNY1vzP//yPXRXu7+//67/+6zPPPFPX9Q8//PDII4/s7u4eHBzs7++//vrrMtpDCDg4ONjY2NAeNXrCxrVr11566SWnlO85ofymPZ6Q9QQ2I908zdXxH3zwwc9+9rOdnZ0/zHjiiSfCMMTvX/3qV7du3Xr77bcxUbCljl9XxqvjUaAPDg6uXbsG36/PPvvs0Ucfff3111FM9TvgPIPTHr+9ve004X/66aebm5t///vf8bdpmscee+zjjz9+8803t7e3L1++TBF/EuI43tvb+/Of/+x53u7uLnT8xYsXdRAP3dfq0vHGmrl+NYeHh7/61a9+97vfNU2DNe+///5TTz11//79W7duXbhwgSKeaA4PD4MgeO6558RA8MUXX2xubkqQq2+//fbChQvb29vOj1rkeb67u2tEvH3hhRfeeustnJA6npD1BOHUnn766SRJUBvM1fE//PDDK6+8kii2traCIMDvt956a29v77PPPqOOX3PGruNfeOGFq1evvvrqq2gy8zy/fPny888/D+8LozkUx/qDg4OPP/748PBQCjTCr4pd7fDw0PDcgFOHXvP999+/+eabV65c2dnZmRuGggwBIgZP9nj2eGPNEP94I8Rk27affPJJGIaPPPLIkAikZK24efPmU089pUf5dnZ2fvGLX2AMB2vu3r174cKFX/7ylzs7O0ZEeRlL1A5gGxsbv/3tb6njCVlbvvvuu8cee8zzvOeff/7ixYuwJw6c5yrB49ujfjUiaehXs+aMWse/8sorP/nJT/Tnnw4PDz/55JPHH3/81VdftXX8vXv3ILvB1tbWtWvX3nrrrbZtb9y4sbu7K5ueeOKJnZ0d+8NS4MGDB2+//fbLL7/8yCOP/OlPf9KbDg4Obt26xbiTx8PW8fgUwM2bN+V3HMfL1fGaDz744I9//OP29vaVK1eMS7z77rv85teac/v27aefflqLeHy65caNG8ae//jHPzA/xyhFKIH37t3TK3VNRR1PyBry+uuvX758Gc0T/Dnff//9jY2NV199FTv06PhXXnnltddes/1qfv3rX9++fRvxaqjj15nx6vif/exnTz/99F/+8pfNzU3R31evXt3a2nr99dfv3r3r1PGe53344YcYzoa3NCaroaDLSPfOzg4+72JffX9//w9/+MN//Md//PjHP8YENc3W1tbm5ubvf//7M8qL84Wt4zH7/oknnpDf165dc9ZEt27d0r434Mknn7SnQHTp+E8//fTGjRuXLl16/PHHgyAwnuzm5uatW7fs+bVkTTg8PLSnO+/s7DzzzDPOiqJnZg51PCFEg/nu0jzFcfz9999fvHhxiD0eM8Fsv5qtra1nn3328PCQOn7NGa+ORxBxlMtPPvkE+hsBZzDA3aXjpRHFi4G/RuR4Z+Cag4ODDz74YGNj4/HHH/c8L4qi3OKtt966ePGi0U6TgZzErwYffNVrhtvjv/7669/85jcbGxuPPPKIDtql2djYuHXr1nLvl0yaDz/88MKFC0mS4O9///d/zx2Io44nhBh8/vnnjz766Oeff66bJ9QV4tvZo+O1enH+po5fc8ar41GgjXKpBd8SdfyDBw/eeustz/M2NzeTJMnzvOuN4ntyEk6i47e2tgydPVfHHx4efvnll1tbW0888cTu7q4ef7TpmTZN1hB8reLmzZuyJo7jy5cv97/7zkhZ2upGHU/IuvHEE0/cuXPHaJ7gQSqmAa3j7969q+fQD9Hx29vbLfXJukId37Zt++KLL/7ud7/77LPPENWkx82a78mxwdQCz/NefvllZ9zJPM/39vZeeOGFzc1NI4cPDw8vX75sxPOeq+M///zzGzduvPPOOzLVlTqeDOT69esvvPCC4TwD/6ueoJNOezy+Xoff1PGErBUffvjh1tZWazVP29vbeoRZ63ijBZRwNO3RJkzW/+///i9CcVCfrCfT0PHwCRNHauw20D9e63jDP14OlKCEdgIM+J4cj08//fSZZ57Z3t5OkuSpp57a3d19+eWXX3jhBWy9c+fOCy+88P3338MJHqYFzXvvvXfp0iVDVB1jnit1PJnL4eHhK6+88vDDD9teNPik6/b2dlcN8Nlnn+nINuDDDz+UNdTxhKwVd+7cweuvm6d79+498sgjOtKG1vFPPfXUV199JZt0s4Uvyv3Lv/wLfhi+pu+99x71yRoyDR0v5fLOnTso0PhYsVPHX7t2DXNKrly5onX8s88+K59XfPTRRzc3N7u8XXs+I+V1RDcnPXz33XdXrly5fv06Mvzw8PC55567dOnSb3/72729vU8//VQH27558+adO3cQsE9ck69cuWIHehcdn+c5Ri3fe++9uTo+CALnY3388ceprsjBwcH29valS5fQTILt7W3UG9evX0fQia7eYM9p9/b2PvnkE4Sq0O46hJB1QAub7e3tIAj01s8++8zzvNu3b3/xxRcXL14Mw1A6/4jEgN+okaqqwqzZv/zlL23b7u/vv/HGG59++umrr75q2LbIOjB2HS8h4YUvvvgCjuye57344ov2gdqv5sqVK999913btmEYypuAv9evX+8q7jhP1zzXhx566JtvvlnuLZ97Pv/8cyPK58cff4zAoE5V/e///u+3b9+G7r9z544RDRDs7e1du3btwYMH3377bRiGP/7xjz3Pe/LJJ//v//6vKxk3btzY3Nx0znO9cuWKHV6QrCG7u7uINXnr1i30J6Wr+d133zVNc+HCBaMNngucyjY2NjzP+8UvfvG3v/3tlBJPCBkn0BVJkty8efPhhx82hE1d1z/60Y+kBdTfk/7mm2/EZUBs8D/88INUIw8ePHjppZeuXLnyy1/+8tq1a85QWuQcM1Idf+XKlZ6mrq7r7e1tfJVTr//mm290L1b3AZIk0fLu3r17PaEn9vf3jbDxAmKcD78X0s/BwYFY4pMkkU/nyFjk/v7+1tZWV4w//Uy//fbbK1eu4GOxXZd77733/vGPfzg3UVoRsL+/399Rv3XrVlf90M/h4eHm5uZ///d/s6ElZN24d+/ehQsXfvrTn25tbXXFvJbWsKuK+O1vf9v1DfK///3vDz300GeffbbMRJMpMEYdf3h4aH/w3MC20xPCIkFGDosoIevJwcHBN998c3h4eHrdeGOmH1kTxqjjCSGEEEIIIf1QxxNCCCGEEDI9qOMJIYQQQgiZHtTxhBBCCCGETA/qeEIIIYQQQqYHdTwhhBBCCCHTgzqeEEIIIYSQ6UEdTwghhBBCyPSgjieEEEIIIWR6UMcTQgghhBAyPajjCSGEEEIImR7U8YQQQgghhEwP6nhCCCGEEEKmB3U8IYQQQggh04M6nhBCCCGEkOlBHU8IIYQQQsj0oI4nhBBCCCFkelDHE0IIIYQQMj2o4wkhhBBCCJke1PGEEEIIIYRMD+p4QgghhBBCpgd1PCGEEEIIIdODOp4QQgghhJDpQR1PCCGEEELI9KCOJ4QQQgghZHpQxxNCCCGEEDI9zkjHe3/0uHDhwoULFy5cuHDh0r8sILBPT7sfucyqc4QLFy5cuHDhwoULl/EvCwjs09PuhBBCCCGEkFOCOp4QQgghhJDpQR1PCCGEEELI9KCOJ4QQQgghZHpQxxNCCCGEEDI9qOMJIYQQQgiZHtTxhBBCCCEroGmaVSehk6601XV9xskecy61q04edTwhhBBCyGlRFEVd185NSZJEUdQvBPM87zocZFnWs0NRFPYOWZZlWdZzzrIsfd8visKZHt/3q6rqOVxOov/Gcdx/0a7DkyRJkqR/57quwzDM89zeNPCiPWcAXVvjOE7TtOfMVVUZWbFEqOMJIYQQQk6Luq5933eqySRJ4jjuPzxJkiAIsm6CIAjDsOtwyG5DR6L/gN9ORZ5lme/7zg6GPtZJWZZIled5ctdlWeq/9uVAqgiCAB2JIAj6hXLbtnVd2+ev6zqO457rtkpk4ww9/ZMgCJw6Hs+3J4V4BM5O0cmhjieEkNMliqKuFnHlJEnieZ7neVEUDTGwCVmWhWE4t3E9PaqqQuJPO2NX+/iqqpprrz1V6rpO07RLhZzZU7DJsmyujXY8dMniIZZm6PieHYIgME5S13U+A4I4P0oURVEU5XmOhNkvsnQw6ro2RHAYhrJG3xGKShRFKBIYBJAd5IqSKn1a7JbnOe5F3w5GBqqqqmcURREEgdEzgQqHzm6aJsuyPM+R1CiKyrLEsfZABHIAO3ieZ49syC1oHV8fJUkSjLqg51CWpbbB475cj24JjF3Hx3Fs9zKbpvFc6LJlg4IrO6M8lWWJugk9Ns2QgZiuN9M+GzD6lGma2jvIb3sUJgxD2er7/tzkETARoaYAACAASURBVEIGol8usERdMlodjxa3nZmLpO0sisKuvnRjn2UZVq5Qx/u+v/Qn5WSFj68oChHQcr8AGst4Uj1G2WMjrZJTx5/ZU3AChTDCN8sGPhtN0+R5rhOsNautmGWfRXV827ZQODhnEAS27kySRP5Kkuq6huD2fT8MwyiKwjA0ugGoCvAbAwX2zXpHBTEktZwB2skeiHDqePzNLYwCKToedwQVh/sKgkC6ELgj/QhQDdZ1XVWV53noMGRZJt0YeQe1jo/jOLHwfR9nQ/7IW7O+Oh556nUMcyCPpBWB0cLzPLs0N00jm+ThFUWBlXqUBG358LEPY9jIuVWuKCk0qlo7GegG+L7v9Hgb6JdGCFkUiJJ+V9QhpGnary3m7qCBbemESbLBMHeP1yYMDVIfwsYmTSAU5LF1/FIsqaixRyLjlv6YYIbUpRHqxBAEaCgXHU5ZCDz6rpbxeE9hWdmVpulp9F5OjzRNi6JIkgSGYYhmcSmBoDQOgQqsu3Hq+P7D+8cBqqqy+66wN0PH61PZj97Q8VVVwTNehHscx4aIh7jH0AHyBK41VVUFQWBcQtdayEyAFyEIgjiObc2N38aNN00jvRSYJ2DIB9IlwL0YfjXGvUvO6Gy3fy+dUet4PNGupsJuRZqmQTNsVGeoZZxeTXh/5C8E9MDaECM7PSYQZ+2GlfZFjSoSN2IXX2waSbtFyDkD790J3y9URD0nmbuDAdqzkyTJCRqtnuoOO+iqCZUVEnMSHV8UxVK016h0/NIfkz3CjLFonXWwUp1GN09j9OjsdB7jKSwxu1br39UPJKxou6IoDCkyxK8GKtA2SAtDdLxxiIzFOYHXHMydtTVBtt85vlU6Ho7yKJ+o9/I8t0U8Eom+jdjj4diDDoCIe2AYIKC20aGFMw/6NpLVOpONDIdqN5LtvJfW0vFVVaFzkmUZet06VdTx/3zkeDDO+3e2IrZBHU1R1zwSwySwkI5HKYeUdx7irN1QIer0dOl4rLdbO+p4Qk6Jpeh4NDM9J5m7g+aEZu8eUBctpOORGFRKx04YmthzpuOX/picTpuGjq+qKgzDMxieXbqOX252wQ46hmLgBLML8JjiODbSuah/fO6KXZMkSU8xcIrI/uuiD+k80Og3al8gmasq/vHGCAMGT5x6DDpe+9VgNm1Zluh1wN2lnVUg9hlq5R/fHtXcPTpeF0JDxyNXe3S8gKoSU5lpj///oAS0LrcTYFcEcGMy3mc0zAMj/gzX8ahA29nzc74PztrNnjrdpePFHcjo+465wiJk0hg6XqZywn4MCaUbUby8QRBUVQVXGcPPvmkaPRHQ3kEm7aBOEHdnXb0I2j0dSe0KggHEexAnlErGdn93KqqBOt7OHD1BSM5suHfr2+xJqr1VKyGpY5PZbF0jN2S9PicMinEci68jnqBOuVTp9jxOeSh5nuPu7MeE8uB5HryNkTD7ruVy9kOEa7KxUut43EVXWyC3hrvT924/Bcy2appGPzidJK3jxd9V1vQ/hSHZ1Z/g/new7QhUMiqgTWGbNzbZeto5F1ZUoLMP3C9a8pkXu6bHHo9Xu6oqUZ+wOovfvDaNw3veeGGl8BunxaPs8pSGjjf8znE2OEWjdwH7qX0G7R8vQxCSgU4dn1mgIElvJE3TuToe/Yo0TcuyDMNQJhpRx7dSsaJI2TWaoeOzWZAjXZ7gAOoNNhUM1/ESBhXjBs5Zp7aORzVneMv06Hh4bnlH+wnU8YScElrHi9qQiVyoT6QuStNUWuVEBY/DG42T6En58trqHdpZtSAqBFfRNlfvqM5OVNA30Yj2vWAGETbVdW27Fx7DHo9DUB2JpteZI5mg9wSoKtEcYgrdwKTmKmQb9pTbx55i8ENuyB1J2uScGAcXMY1cRcqhtPR5iqKwHx+0iMTWkJpfPyZ9FHQAihByzGjOnRGpIR3szhXODB8Dp9elzmrkEhoRSWd2NI64HsGGIMM5DdcFwx5vWGR7nsKQ7OpJ8Nx3UJDDxwnEZeKarGlEcclmsVP04UmSyPtiS0kc0tONGWKPN2yLyE+oUhQ2dBox8bpfgYiHMwp/O4tjA/+iJEmcsY+g4+FaY+h46OlWTZaFu79xBnHfkJduiD1es6hfjSRJbgfzmPE41l3HF0Whu61O35UhJiWpBZyjkxptjJmr41HRyN+u6KR2BAzPFWemR8e3s0EGfX7qeEJOCcMebw/6aQFqeOXKb0Omt9aUd2MHrWLtqxiKx5h/5pz4KBfV6yGA9LEDdbwRo0Za0P7MQf7oy2UqSqCxZ39SjYAYkBdyCc+ylKMuhR1XjkImIwFGl6PrPHJR/fiMWZXabG/khvQcdJYagrgsyx6vUbtN0TpePwsDwz5tF0hJvHGbkidGF06SDXnknIHmfAoDs6snwXOLmaRBt62YHGlb7lcIzMnNLB6iVu0S+0Uw9ICWnkboQxjI4zg29CWiOopdGerWsMfDHKl3kMPxiG31Cat8/53iKDxQSHbpPULjSlJ1QYKOlywKwxAeOOjqSBZlai4s8gSOPcgHozwP0fFQ3pKfWseLFcCp48uyxOefxKmpnn0lAEMZ667jjXFVVCKGTNevN+oju48lWt/5MusxYjBQxxsTdOzzyF3o2q1pGgk0mVvRabp0fKtGFST62LR0fFeviZCxMUTHi1zAmwtbmj6JLZuMqsDYwRZtPTre6RdhqzTIVmMQH42rpHagjtcYM/bszNFtlbGD1n/6BvuTitpvoGc2Eowb1FGGBVwUWTpcx+ut2GTPQO3S8bYJSd971+ct7a6dHC53oX26nJnTzixizlrXGNkQYDrFIZIAGV2xTcX2neqnMDy7uhLc/w4KxpwT8fBxejOvhGzmKmys7DelA20ygJQsyxKqN5uFVjTQK9H5x/hSHMcSa3tuJ8dQn3hqYRiKsdx+su1sHMybOZWJMMNMUDiMiYuObIVhWwdcx7HwopHQ7KLaJVZMNvNtRl2RW/7x8Pjq0vEy9mX71XgzLx3P0vFw3RFDA56O0R1dax2v3e80Ri4Yr7czKA2ytetltmvzgTo+UFHeNf1WCoDaU+88V8e3ahaFMxrUyKGOJ1NhIR0vM1i8ox69p6rjMWdu7o1krvn9hhPOMfxqNEMElpjkjQA1+gb7k4qrdKmxHv3t9C8HJ9HxrdKIep+BOr5Vtu2mO2zREB0vKXF6KWAGFxxg7HYNhkPDMwflWQy3dlFxzteam3sDs6srwQN1vPFOQUHO/U7q2YBQKnYXCAVgyGRfbQbGOAO8sQdeXY9oadEZRVF/lO185lgP7QsNLd9jwoM2AtpgZ9G+oJ2J+OToBFMjSmOi4tnXKsI9TiUDetnR73+hemld81yxp6Qf6506Xvx/7N9z/eO1uPcsh0BxKlsvHe80UYjDoqwxXm+Z5Gp0MbuivrQL6ng94GjXDsYANOiyx6BGM1r9fh3fzmpSOA5OS8cTMhUW0vEAc9d0B/UM7PFzv3EBIWi0HE6n51PV8bKPMe5v2+O7kto12gl6FGTU/fGmE+r49ujgKnYbruPFJJ91f460369G54aMmdgTw+TkdruGtGkhCGdRo3Nl6Hg4SHjW0Hd/7g3Jrp4ED9Txhl/NeKjrWkZOjE16Ug3iMzrPYBjvukKmwJHDvrphMteHo3ct04j1UFuapniDMFzgfI9sYzz6Bq3LQQVyX27ZGaVRW/ph7IeO1y524kZvp0fLaPHRRwqlS9AejSXfnljHN7Ngmq1Lx8uB66Xj646IQnZtbr/ezoFC51RRMFzHo+jgd+iK8yWzXXsabyBOMgvZ4/WezraBEHJyFtLxukpB5YMafCk6XqpBp+IxxuKdgg/3oisWww39DHR8OxNYRq2udXx/UmWrrqjhV9D2Kkjx6DBcNNsT+9Voo6+YGIfr+HaW8373F/3657kavRqR8l0eU0a75pwbbRTCLh3vPLz/KQzJrp4EDyxmcJg27mg8A79asgO4ixij7nZUytaK194T+tCegom4jfDhBv7sg6OQ6eibiV5vZ90GaPQsy/SbW9c1xpFwctugqSe2igiGRVzuGpMWbG8irbIk05JZJErZR+z0uRV/09bxelAomQWnN8ZA5up47UBvZ759iPb+l8pnjXQ8JoI4x8LEQ8awS9kPHtWczut6FqxAe7I2syBZdm1utFsYHEGzgY+EOROP3oLxvhn1eDaLFqeTbQfWbFRgB4OetoEQckL8o99zlYFj/K2PRraFG4D20YRuQMWC0ChVVYkSFeOTsYMOUFPP4jmguhNrEKopPR1I0xWP2VNTIZFCbQALrW/SGUBdde1gZI7TltF2RAoXmS5hKHqSKjpV0LE7PGuEwXC21BgSX1JuxDpL1Vc+jMeHiZt40FA8mZoMJ49JzumUkoaXvBOnX1DdMa1ZCkySJJgmKPkgkw5R3pztZhzHOg6MhIDE/pKTkrFGm9XzFAZm19wEd72DOlt0QUWp62pGzx7bBuycgwuBYaw3pkB06Xgtl9u2xcRQ/BZPGPGxkb/NLKyWMZ6DH7b6xBo81h4donW8sVvWMSWgS8eLF76AgSM9LVtf1DmJVkz4mRWt1RbiiFifzVz89SWcwYLkRTYSYOdbV3adkBHpeMMtXme0HZrGQAf90c7rhoY2Zj7p4Fk6bq4Nev9SV3pHtb7t/+2cYmVfVIYa9Wl122NbHXCD1PGELBdb82m5DC2ityJAuI5pLXUC9IrneZgIZbzgxg44RKQqWiaYLQ3XO938aGnb41+LoWqpeaRhs2vUudHAnHFXejJH72wbnrNZ6BtZ35VU2aqlKsSBkbG6DhcJLivFRVin3J99alAQ52w5yrgKul6o4Q05oh+TcU770UTzPsKaWd+B0g2QpzpvxnrkvwS0EUWCXPVcoKFJVPR3mdEoZVUuqk9itHT2UxiYXTLVxEjw3HdQFw97Zqc3wAPtbAjU91ahRLWNXOZ9wmXc8Juy+8B4CtqVHLML+ic9y+G20OxSFE71CRuoU4sLhl+NrEySJLCCzcu18FIIOiJN/y3AKQjFwzltIOj+3q3TBo+3T3f1nZeGHpPbsXW8nkuwFjqeEELIOQPN86pTMS5gVJ67W3g0sCnpwplRCD05EpsXZDp+SycW/RztmN7OVD5+w7feOBW0tRNDqjZNU1sY9vi6rm1XdeNazjvqd7rT4hjGfgw1dLnat932eLkX/EVse3vQD1aArikxPTq+VeMPOtnabwfjD4H1hSJjMqet42Gtl05vVwJOCHU8IYSQUwGukiOxiY4HhJ2eu5szyAkxyI5+KECA0frs09OFnifQ80xhV8Zvp7v8cGDVzofhfEmz7qnYSF7Xq40BFhyO0j63GMPDUK8xejhY0zUOANN411VC19fWbODv5MxzDO7pbhXGY419jOg9sueQoZJjQx1PCCFkmYhP+alaoSaHWOaG24khXIZIkPVkrqM2OQknzNjTeC4TfdanmmzqeEIIIctE5imNJID3SJD46wtNvqzr2piZR0C/tZiQNYE6nhBCCCGEkOlBHU8IIYQQQsj0oI4nhBBCCCFkelDHE0IIIYQQMj2o4wkhhBBCCJke1PGEEEIIIYRMD+p4QgghhBBCpgd1PCGEEEIIIdODOp4QQgghhJDpQR1PCCGEEELI9KCOJ4QQQgghZHpQxxNCCCGEEDI9qOMJIYQQQgiZHtTxhBBCCCGETA/qeEIIIYQQQqYHdTwhhBBCCCHTgzqeEELOD03TpGnq+35RFCtJQFVVURQ1TbOqS9d1ffaXJoSQlUAdTwhZd9I09WaUZWlsDcNQtvq+P/CcoqflwDRNz0DdSmpXouOLokAXQmepkW9VVelNaZpifZZlkl1YKZtsgiBwbsVJqqpa9p0RQsgYoY4nhJC2bds4jqE4nQbdhdRhURSe50VRJIcURRGG4dlIzCRJVqLjy7I0cg+dCuctZ1kWhqH8jaJIjyHgFuI4dl4oyzLP84IgcG5FX4JWeULIOkAdTwgh/wT24CAIbMO57/sDrekQ8VqkgqZpgiA4AykPW/jZ6/gwDLMs02vQNXLmW1EUItPLstSGeZCmaZeOD8MwCIKee0ySxM5/Qgg5f1DHE0LIP/F9H9LTVoHDdTwkpu2f084MyactMVei4+HQYmTRQB2Pno+h2pumSZLEeWAYhnme9xjs67pelWcRIYScJdTxhBDyT6BEoyiCV4y9qZ3Z7MVdRBzBYU6Gvuxyo4e+hMrXE1LFNdy4aFEUSAw0qxbE2gHd0Lu2js+yDL0LXMLwOZGrB0GQ5zlWQoIbLuzGvWvCMDQS3w7W8U3TyO3rnQ3rvpwTt4ZDuvxngiCw00MIIecM6nhCCPknEOtwgDH0sTY2G27fsLLL1Mx+izvUZ5ZlItCjKIIwxXlEvOZ5Li7j6B6IMA3DMAxDSFjbxm/o+CRJ5DzwHdfu43pnXAVkWYZNOhMguG3pjP6JPfF0oI6XuzC6DTZVVYlbPJLn1Pq49PBJyYQQMlGo4wkh5J+IWK/rWgS3samdzcIUHa/du4fr+NYS3AjkIio2CAItUqMowmkhecVwjk36QH1anFNrcUP3+75vzDfV80cxN1duPMuyLl8Xp6QeruORVB0ayCnQ0zSV9bi1rtmuyAQGriGEnG+o4wkh5J9ozQp1LoJYbzI0otbfA3U8VLhTx0Pd4upOD2+MFWiFCju6YajGsehyaE0svj0wqwdBoKUwlLcOs2N0LZzKGAk4oY6XU2kXIL0JowH6bND9zlxCd4Uu8oSQ8w11PCGE/BNDJkILIsLMQB3f7x/fNI32L+/R8RDQ2uiuE2noeIh+uag+LZS0obD1GbQpva7rIAiMToiY5DHB1Hlf/Tre6cKuTftVVRl3Km42er32vdE4+wPU8YSQdYA6nhBC/okdcQWaGPEih+j4dmYvdypI6F1Rw3N1vFM34/xa4ELHi/XatscbzjBwkdf3KA4txmzaVpnk4zh29ivabr8apKQrdI/2kLHddfSsA7lxezQA92Kb/OlXQwhZB6jjCSHknzgVoURuMXS8yFPDB90Q60LTNLBtO+eYtkd1vIRw0cbmPM/LsrRddwxzuD4tFLa+L/jVyGkxn7U/W5DsLk/0tnueq+GWo7NCi3IMdxhme9yU9BzyPHfa3XGz9iUwu7f/vgghZOpQxxNCSNt2B2NpZ37YerqnCHf4eUPoi9KV8DIiVfM8x9eLtIXYcHoxOgC2G4lsQnogXuu6NmI+6q3tzCQvO2Amq9yLOKNrDMt6lxw3ssgZ5xH3aEy0DYJAn01mrGoLPWLyyF/f950zXyXGjjEAwriThJB1gDqeEEJaHSnFtuPCfqxN9RI1MssyqMw0TXUfoK5rHeLdUK7GFRGGxU4AQk9iZZIkcn58I0l21gJX9jeM7vo89hwAG8MZZu5naJ3fgZJN+majKDL8c+AfD+8anSd2Co1RDp3D+n75HShCyJpAHU8IIetLmqa2/7p8awnkeT7Eth2G4VwXnbMBHv+rTgUhhJw61PGEELKmwNvHXp9lmVjW4dY/xLaNcQnnrNazpCzLLv8oQgg5Z1DHE0LImiKTRLU/DCz0MtHWs+K494DvxXaFtTkD4InEMDWEkDWBOp4QQtYXw3ldvPAxJcDriM7eQ13XURQ5HeVPm6qqoiiiJZ4Qsj5QxxNCCCGEEDI9qOMJIYQQQgiZHtTxhBBCCCGETA/qeEIIIYQQQqYHdTwhhBBCCCHTgzqeEEIIIYSQ6XFGOt77o8eFCxcuXLhw4cKFC5f+ZQGBfXra/chlVp0jXLhw4cKFCxcuXLiMf1lAYJ+edieEEEIIIYScEtTxhBBCCCGETA/qeEIIIYQQQqYHdTwhhBBCCCHTgzqeEEIIIYSQ6UEdTwghhBBCyPSgjieEEEIIWQ1N06w6CcvnXN7UOKGOJ4QQQgg5Req6TtPUXl8Uhe/7eZ73H57neRiGdV13bSrLsmtTVVX2pjAMkyQZkvI8z6MokpOEYZimqTMlmiAI9P3meR4EwdzbJMeAOp4QQggh5HRJkiSKIsNQnWWZ7/tzZXEcx1mWtS47d57nXWeAepa/VVXJ4UEQxHE8JNk4iZwfd2HsYB8VBAESDNI0HXKb5BhQx5OzIMsydOKPcWxVVUmSeJ53vHG6LMs8zyuK4hjHTou5mRxFke/7HO4838B4Fobhsk7YNE0cx2f8Bp2kxlgtSZJo+UKIUFWV53mG6o3j2JDFmrquwzDE65DnOUS/YXo3xHrPpiRJ5PAgCLrs8WmaZookSSDKQRRFURQZW6V+QP1TFIVhfTdkPVki49Lxvu97nud5Xr/aCMPQm1EUhXcUdPuMlca4UtM0xg5Gs4fCKluTJMGgWFeqjCEk4xL2W2ok+3yXbyhpPJpFj9XZOH4d3zRNmqZRFPXbOVApe57n3K1/a88552YydXwPdqUhNcOQQeSlk6apUa0ZlYbv+9jTrs3sCu3Y1HVtNMBQErqwLV1tL1RjyM4CanvdTJxZDdC2bV3Xc2sAslbUijiOy7Ks67ooCrxWxvtVlqX+W9c1FAIOR0/A0DNzdbzU+WEYSs3Qo+ONNsLuDPQ45GBwoCxLrePLsvR9v6qq+igyyEBOwrh0fKsEblcNjnJs1MuoynXZaprG9/1+1VKWped5xguA7q+RAGkqnH5m2Op8kdArNdKmD1yT6h6P9djtPfJw/AI0DEN0/7oea1VVuBdnn7B/61yOkckD/SPXBNQtutddVVUcx3j3z96zExpa13VN06B2sh9ckiRooSHrl6Ljm6YxjGroCkp6MFC2rEqsKAo586KFGSkxNAGe3UqEQhRFfLlI27ZQq3g94ZKugXO82LbRgsBuKIfrygd/DbOC6Gz0EGR90zTYBIs+RJG8DlrHl2XpdK9vmgbjS/pNTNO0pzJM0xQVAqoOnDZJkjiOYZuAkRRbgyDoGYsgAxmdjoeU6ZHgcRyjJdOSGkraqPRxkv5rGQ0e2i3P8+wyDdHfNV/EaG410gewmxPj9TjHnFDH44mPX8e3MxXlVDZVVfm+3zVXqX/rEBbN5KIoluh9cQ7oenZiXDh7KY/aQ1/XrrWADG0vUcej9ZW/qAONAibN9skJw/DYOh4SQdfAGN9flT9uXde6w0OI04wNvxT8hs42KhkId4hpAC2hXV/E7wXdADk2iiJoZXmbdJ8BGlr6D2EY2i2s040nDMMeT3f0VXD+OI6RMIwJpGmK/kYcx6L12d09OWPU8RjIdlbiUPnYeho6HmfuapacTqIQQ3medx2I3idGoo1XlDp+IOdAx6OLqGcLDd86kIUyGbZe6nhNTx8MNUPX4PXpgVbcMFnZtgaM++H3snQ8qkdd46GAGfkDi90Jr9VaQvyEOr5/6P9skBESQlqrTKI5i6JICjledkM0d9njdWvo9KuBZ4FsStPUSMBcDY02Ak2SWNZtF3/9Gw0Z0iZDeUmS4Ie4H4srESPYLIWR6ngUVtskD2+q09PxUNvOAaa2bcuytHW8iHsca+swJFhMevrka6jj0e1Btuu8wuAjskiP/QGt4/M8j+MYZcPweZChD4kJABuAGMbErxeFR1yQ8RTEYJBlGao/ORV8XocYZbu0oAwpOo/q39q1P5SlpKc/k/V0Ydj+vRnyChRFIbepjaPtUQ+xPM/l7ZOMQl7hcjrbxZ16/OOnPToeNZJ+f7vySuczfthPVvJkSDOGq+iXBcfqNjhJEqlJRMdLoTUMw85HZoMnaOSPPEpdMxt3pz37JZHyqmJnqQ9R9mQrgINNf41hpxYHinzpyVJnCtuZzQVuA/q9kOdlVE39OYmTdLUmZN1Avw5iGobqoij0kBc8yw3N4/SPx2/Zx6njYaTXmww70VwdH0URSi8Gl/A6oFqIFJ6SXrDuy/nzPJdom3CRl1uAC9Dc9pQMYaQ6vnW5NsIY385q4aXreIwae4vYfSVJbbcUE7GOROoBqXXT8fDSa2dZLfUXqgnReagadBUjOl6eke/7cCIXVyjpUOnCIHPdRMcYTll6Z5FlGI6UreLqimv1T7ro0oIojRhhtAVB/1YDPXiK20Ft25PJzunCUjUDyA4cK7NEkA8QcMg0lHn8xhX15ZAwnZP6oYx8SlOPjm9nVnDcQk9eSQcpjmO86cgN0XPacozzaIFro6/VzgJCe0cHB+TpyF2I6UuGerC165E579c2J+tJpc66CwP0uHHsLCcxXNhxda2VPcse31Vj2MhQ6txi1pVCEfeQL+IDoKPs4VHqrkhPTqJ9GXmZJ2cGFDwkOOQ7ZK6UxjRN7TcOYhd9S8SrgY7P81yaSFvHiyu8dp03XtgeHV+WJbocuKi4waAy0dLL8Nc37P3a4iPNKJq51hpqIMdmvDoelaAunTK1+ZR0vJiIhut4+Kjps9ndYi3W0ZKJI9q66Xh9s1pEovWVukCkuSG+tQDVT9YYUseDkCYfeW7MzJPCY7j8GnLTdlFAUp3TJPQhhuCQZh7JEOVniADnVgOYBnXGirW1P5Nba7qwvVWXXqQKnRZcRQ7Msgw5AIkpuaFP6HwoIy/t/TpeT3/vyavWKq6GQjWyHVO++lPl+77sg+Zf9w20U03bXWhlOKvrkQ3MClTRzu6H7c2vzXVGh8S4ulPH9xRmA5Q3GQDpKmn9KbQdhzByJY8SygO5PTcn+4sTWTf0d5e0i4uoCOm1anrmuYoQd9rj5X3HJsxz1TtoHW84GsB2DsWFGYmSbOM8eGX0rFx9fpjni6IQY3yrvGtwL5xDcnLGq+PboyZ5uGph/Uh0PNpXvTOaN6NcGmIdzQYsN2uu43Wn3HhSaI+lljmJjje2GoXH0JenpOO16U5fFznQv9WgJzR4TyYDOxvlVM4JHtD9sKl4agzEvnQ2i9Mqz6X/oYyTgfb4/rxqO3S8Hm42zBP9Jao9atFHc5ipCF1GwPKuQmt4fdiPTIO3sud5GS4lOhP0vSCvusr5ojq+p8Mj5U18xpy2xiEpdEYqMzDcirpysr/vQdYK7USndTyMXpx0DwAAIABJREFU310BJUXbGPb4dlbmYZvvejWMTZgUC1A4MdxkT2ZFCUfacDkJiAlTgpzfrlvaWU9AvgKLCbXt0U9WdR1LFmXUOl6rGW35PiUdb7vA9tNVxRuNnyHWJXKc+PoPudbUcbbKeDqiEfX+yFvJyfOn41tlHe/fapwfwZGcl+7JZDm2S8cbGQ60F4H2ANG7oV6GU5O+3DnT8bpymJtX/TpeP+6Bs42R+YhSB9EshmFYE4xgc/2FtuuR2fdr3GNVVfZMfWSL9inSb4eMVLTL0PE99bkubxK/1XYZGpJCI8Rez0Xn5iR1PAF4T6V46+mt7cxV0vmdmXyGBP8Q7VsUBd7Q4Toe7unw7YE9XkK5221NWZbiHIgQlnIS8fw0tHhVVdks+o0/i72TzWLyYKRdbpw6flmMWse3yiSvy+IJdTwm4bWuea7GpI1+DEcxfVHDWmOcUMJCB9bXo84rPa2yKCT9PhvSZ+o6XmKH6ZWo6eZuNXCO+YCT6HhtlRQMx+525tooN2h4KZxjHY/bQXbNzat+Hd/OHGGlUzRkABB5q03vUlk53Tm6Cm3PI5ubFZjCa+yp6149KAG04/iZ6fhWOac5Q/30p9C2x/cEFO7JSfrVEMFw0DImuKMs9RsQwzCEqra173Adr+mf5woHTszHhWu7fnPlG7S2vV/ku/jH67Y4UB+lws6TCEM3csau48XXxWgFT6LjJQqSrePR0ex6o7Q5CpM/7H2k06zTZot1Gfyljm+Peh4Dw4t96Tpeni92lurslHR867Kj62q0f6smnQVA1NpCe/ceT8dLKBJ9WvEAQfwQ+16MzsZ51fFGsKn+vGrn6fjjjcJJRBc9S96uG9t5hbbnkRnYAwWotZxRWVAx6t6O3mpPDJWrS6YtV8e3auRTR9cZkkJ9UbHWG9MA2gE5KZFGutJM1gdYqeWv1vESPqFHVYsCPjMdjzhRMhXKQALmyHRwvUnfo36jfTUdv51F1OlKABnO6HS8MWernVWXutOGZklX2dpbFDQd33PV46TO77mitOFsevaG7o+iPXNW0OJ+oIWj823Bnmui47NZ4Bf8NZ6OdJ9kvqbOXkM2iR+OPFljFAWNsSGqtIqSooJxSTyvYPZ9Cn0qY/6ifTYbZ8BvuUdZDzuHnj/Xs1Ujk4A1OiZMVyZLNkofRqSnnoYYzGKTaRMRnojEroFlSHJeXx06TzJWMsoI5DdO7M6GfM/Vt0I3duVVa8V3R6dUCpX9+IaoPYnfImucA1mtckc0Ci3S3/PIjCvaLiVyZl0TYgxd9tF9chjFpUDqADWoUf1ZbB/4+CIfMDTfX5htEtf3XKWrE6pIlD0pdHpMydxZYW7hx4GMO0kExECT9k4XDHjYoglwSgWMguI1PzMdb2MEuwQ9Wlz3VeAub7wLTlcicgzGpeOlWteVaVEUhtuDoWCMNWh+7JZSgHnGWKmbIol+LVuTJDEiFdpHtUfDEtvYTfWa+MfrbJEJPYJEM9TRuOX9N3Y2CoARBx0Vot5BaybJarkQRIPv+2maykB816mMazkfnB0GW2/V9yh+hwO3apqm0XmVqSBOPZlsJww3qN3DJKah53kyRaltWwQcEEEjtb92RBbJq51G8FfnZI9JdbV0VRqGJ6vgzCujYtEdRe+oM5LNXMFn2w7shtCoD6XzBlDgnY/MvlxlfQcKA5ISIF+erz5KR823Eyz3jqyAcClmn6FFfiIWvpy/q8awz2nsYK+X2HnOFOqLGqVUn0rud25O8jtQBJRlKZEtMJiJHikaHSmBELvh0a8fZFmG5kD3AUTTA8PxWDNcxxtz5dG1hmt7FEXS2cAO8kOiSTrPjxuRibw4UBvv1kH/nAHj0vGEEHK+SdPUluzOb0WvHCrRY2PMayTrjLbLoP9fliWixxqdUpHyUNXiA4wDEaNWdDx61Oiod72nMpcU9tBMgWFV/IZZXVQ1Orrwj5dhBA2MNfZsEw10PE6uvQExDozhNU5yXQrU8YQQckagFbfXZ1Z05zEAGzk9vI9Bj52SrBVFURhqFQP+XfLXiD1lbLXfRzg9do3mocIR18qBaYYxvn9/DAv3THnC99TshKFWEQs9OTnU8YQQckbIPHjdRjot9CMBQ/8c/h7OXH1DyHJZlQng2Ncdoc1i0lDHE0LI2YERbfG31oPOo2Wcbj/jxIjQRwghpwp1PCGEEEIIIdODOp4QQgghhJDpQR1PCCGEEELI9KCOJ4QQQgghZHpQxxNCCCGEEDI9qOMJIYQQQgiZHmek470/ely4cOHChQsXLly4cOlfFhDYp6fdj1xm1TnChQsXLly4cOHChcv4lwUE9ulpd0IIIYQQQsgpQR1PCCGEEELI9KCOJ4QQQgghZHpQxxNCCCGEEDI9qOMJIYQQQgiZHtTxhBBCCCGETA/qeEIIIYSQ80/TNCfZeaHDydlAHU8IIYQQcooURRFFUVVV9qYkSZIkmXuGOI7TND1hMoIgyLJs4M5ZloVhqNMchmEURVTzo4I6nhBCCCHkFMmyzPf9siztTUEQzBXoeZ57npemad1BHMfOk9snieN4YJrzPA+CQP42TeP7/sn7EmS5UMeTMRJFke/7/Z3+IfsIsCscrwJa6EJdVFU1HjNGkiTDTTJkCEspJAZ5nkdRFIbhEs95/siyzPO8oijatq3rOk1Tz/OcVs+iKOI49n1/0UvkeT5c+iyXLMuGWGrJ+ImiSEpRnueyvqoq/Y4765CmaYIgiKIo6aW/gYMKj+M4SZK5ij8MwyzLsizTOh5dkZG0YkQYl473fd/zPM/z+stKGIbejKIovKOkaap3ENCP1Ke1d0uSxD4QBRqHoM3QDKnfWfoXZbk6Hk07ysYpJaafoih834fU6N/NLszy2655dQGWd2fInnVd60aFtKryMYiiaEifZ+k6XgpDj46P41jS2VO6dCmaWwhPCdSB+jVcllVP63i5hK3jq6qS8r/Q+dGg1HVttBf69THaBSSmaRppUODMUNd1V1lC8pxPJ47jMAzZfEwaaGgI8SiKPM/Lsgx1CyR4PgP7GIf3l4GyLOu6npuGJEmCIGiaBoW5/5AgCOI4NuzxURTZAwJFUcw9GzlVxqXjW9V6ddXyUh3rKg/VqC79dV3rJrBpGrR5dqOIql+XQtTXeGegeIxaG+3i8HYoCAK8twP3J0tHBiWH7Gz0905IWZaQzgP3twszim7XSXzfF9UyfM+2bZ0NxjpjVBpt2+Z5jtpgiRk1/FR2emygD/p3Q/2zwtFwdHKkxoa6PaVuJKprpz2+bVvf9xfS8RjHk7/Iba1sNNp9GQZU0TfSjnS1Anhzu/IEfYnhySZjAwVJy1+UkCRJDFls+9hkWQZJjZ6Aje/7c4sHOtLSLpRlGYZhl1Ue5byqKuh4SZvv+1iDHghqFcihVRkISDtCHV9VVRAEqG2dWgodU6OmliIla5qmsds2HGjUpGgF9bVQpeo1aAilpOJyA3V5URQ4nBXxCkH/cIiUQRW2RB2vx3OGYBfmdlZKYU0x9jdSO3xP1MusfwVnpSFCee5I9BBguzpJemzQinc1pRAQK7QjlGVpl+c0TU9Jx6P2XoqOxwtinKpHM6VpaozcGk+kqyqApOtp9XAs/ZKnSxiGUhikREHHG3sGQaC9buDc0s5MUU4DjfM8GqdrPgxMWZbZRQ6iBWMFUO0Yv8XOOAoWVWj9roSRs2GMOh4VllN1QeXbHpADdbzztEN0vHHgQjoeLzCkfFfrQk6b4ToeZrNl6fhjuFR16fieASVDxw/cs23bJEnYvRS6dPOydDCMbaeh49GUOvdEe7xCHY9Xz1Dt8Dk5jcstUcfDZmSfYYiOR5Nh5HlRFM6nAKMmhim6HhPMsfSumSJQzOLFjiq6HaDj4bWC33jHnW7xOHnX1dM0DYLA+UageRJdrg+RzgNGn+CK06oWTf/oGqEiZ8NIdTwGlO1qCz3CY+t4p9XqVHW8TGGxnSXWCvgCxnGM6Z4wGOMJio+vZE5VVWjS8AiqqkL+y9h0nufGPkVRoDqTfYwHZOh48bPSezZNY7jANk1jJ0b+ivNrT0lAlC69BkPksLLg8CiKtDGjS8c3TYNbM05o6/iBe7aztmEpluZzQJduRiccuTSkNLZqFA6er1VVVVWlXfDlKohGJyt17TRcx8Oga1duGJFH4Ucp1Z7ccmZ5F7APBg2MtxJzPRGEDsZjDLVLSauqqsvYjBs35nkbO4sDPXSMnBDJgO5Bhsi7iTVpmuphJdyLzlX9KkG1yA2iC+TMVbE72rk9RMc7HUQheuwDMXqGgYsuSYQ2kc6ZUwQNnxiw8eK0w+zxAupqOdxwxXFKC7yeiGqQW6AeE399T3W2xRdfdDzc4lvljRnHMdoX2OyXmF1kUUaq49tZdayrLbQf7UxVL6TjpVq3LbJDdDwqfXm7hut4dDzaWatwjFAJ5wBpjGVoWFoseAe2Myt4URRGU63/oioR+6KW2vgtZgkRsvLIDB0fhqF4nmBP0bL66du6QaRYHMc65U4pjKZXFzkRTKLYbEtqj44XuaZrbaeOH7JnO5ttQnEAbN2sdWp7tDx0lcZWeZe2s1pLKitDBeLpI/9lJqUU2oV0PJJh9Nxwaa3j29m7YDS9YRjiupgSgLKNc0pPQEQ2/qKulvqtZ0KwziLnmFgcx5JLmBQuNbwRKU8KNrJa+huGjo/jGDugfyVvASphpMGuJTS4ru2qNFDHt+pl74/Yjb4WfuN2uvrVcI/uOg8ZJ2VZ4oGiOdAmm1PV8fCKkXfK1vECTq7rB0mA6HicR+Z66V4udfzKGa+Oh8LQ5UM08XAdrxHhZdCl46UGt02bA3U8mhzjtOupmSDc9di6nkzcWlmqm2rZ2RgZNPYxukmoNCX/DR2Pyfj60oYOsGdHGIkxUu50TTb0k/NO25nUMHqJTh3fznx29RmcOn7Inu3sNWHgGmBXGsAQT3NLI5SoLiFdOj4IAl1F4DWRYxfS8ZIGuZYIRLscGlPTyrKUZARBoAszzomW26iQsUZ7/fZUbqjYJUv1nvYbpOeq4kXWRdTwfMPrY7y/xpdrRD8ZtUTPvNWu+JXDdXw7c4bRXSD7KP2dHek4Oc8fhuF6WoKmDtS2tsfDgCUTRjU9Oh5lzzauSyfcuOixU6svigoB7ZEY47W/KJ0zV854dXx7VPii0GP9ovb4HufRtlvHa+z540MUObwe5S9a0/Us8ajChut4Y6vx17nSHu7Q7bfTP76eRZvWl+4ajenX8c7CoK2tgr0/0iYGlX4d387Unqdi7Tl1/Nw9Zf/1LJM2tm6uqgrlQdvU55ZGlHbfCnTbHs1t5zdZoJvRKhvpMZy+7O6ZoQK1hdsoctCvuqbFVikwBjJQZhQVGfMZOPMHssDoHSHght5Na3G7q2m8oUafxNbxup9g1xJd82HQPTihjtcJsDswrTXvWYZtnX7wy526Q84McWT3lIM7JPtwe3xd112fgur/AhQG62wrPpzve2QMfEfF7g5fQRkHk5TPnWVLTptR63htkrenEC3kV2OMrmqG+NUYDNTx0mIZrOFs15XoeDxHp47HkDrmTBuXPnsdj8wZruNlHzhv9Oj4/j1lf+p40GX/Ru0hdoQhpRGPHuhir3PbaXzV0QkX1fGtMsnjm0dY6RwXEvnbqABN2NOpCZyZA68h0eVOEyAiWug1omuxvuvNPRsd31Xb9+j4nriTelTNyA0xD+n1ts3IKff7k0omwQn9atqZO6hhj7fjYjuv63SRRyNol6g8z/HFNFyxnU0eE3c7X4WwpI5fOaPW8a0yyeuq83jzXA3fU2G5Ol6mg2ivx550rgkr0fHazqd1fDML7ey89BJ1/EC/GhhBZc0QHd/O3gLMOOzR8T17tvSrOUqXjhfvcO2T3V8aASouncO2Pd4QhXq6xaJ+Na3qG2hvDWc5FJN8pr4Y6owR2Z857ey7s/a9AEwCNlbqQo6SqbcuV8djB2Spc9TO6azS5VfT49wSRZF0gSCbjB0Mj02Z8aXBI3DmM/1qJs0JdXySJPANDtVHl4aYFO3r6nPaCUD7iGuJf7x8AhbumvqK/dM/yBkwdh0vLajt3Lmojkf5w0cN9BWXqOPrWWym9qjXo05Vz7DpOebsdXwz+wY1/modb8ia09Px9jxX5/5GeR6o41tlzOvX8V17tgyCcZQuqYonMtweXxSF9vYWm1Z7VMc3s0Auhj+67HwMHd+o4DCyg1PHt7OC5x8NkY7DdeteFEVZlnZimqbRpRQGbFsuYCDIWI8+DPSKoW5bl47Xt6PH2doBOl532o1aAvWSs9/SNc+166s3eo5Ba31AyplFcK6wLx12fA0A7tT2/mQSaD2N4ZrhOt7obENdwOll7gdAFtXxrXKRh45vmkY6qMaHwHHyrgEEcjaMTsfDB0uvgRHC1tn933O1p8m2s6rZ6E36Hd9z7fF+ccah19EbEH7BeSzsc+tWHeMBaQVjhMlDlkp0OV99eUd21k+ksb7OY+gPjBgajT0SAIsXHoHEwcQco1aNp2dZVlWVfSEdhVD27xpjCa24kyIKdXQOfbhdmJEGZ0VsaMrhe4KccScVqDQMqSrRRcVnfW5pxDOV/cMw1D7r4ijYKpO8jg8jjwP6u7/b36jYOMAWml3DgIaXPNAeQQAJljm4+nB92q5KT6piqXVRVdr+k0izxO3Rk4OlVGNSnX4i4dHo/vKxWGQaUqV9ADzltmS/nkbm2DobRxmbuvI8iiId/9tXcb6xg7OVET8u/SKzyz118AQxIwKlIuj4nqvth+Z0ivOtTzv1XHchHS+IPR7EcWwM3qJaYAuyWsal42Vqv6dstzJXuj06YQiIwV5AfG5jjVxCQqWiojSOlTYb2IOYdgIMEJhJJ0+ObaxoGGviKC9zSb2Z8U9nAhyQuh6K8Xy137CRyWjs5QFpb119fjxTHfpd1JsECsQTzPPcvpDxV5/Z6Z2SWd+BElEVziJYSx09tzDbBRKyUvt7DNlTYKgBQb+2Bgi82FoFr6s0woAtZUy3lEYvrp3FeZRCawzLCM66wi7Y7WzuB34b75pnWXmdwSL1bFQMrxslUyzlUBgyAtDjHy8h9qVg630k3D7kvmFTl0iUuAQCVyPZuszrZkLSnySJ083Msww6zuztmdJqtFbGA4LBVTyOvKM9Gf3gjKzomgWR8ztQE0d6wtokhAmjxked7HgM+rd8+AmdYXsmhkG/f/xwHR/HsTimagMZi+XKGZeOJ+TY2J6vIyE8+kH1gZOkzwBYHOcOy5LzClwNV50KB/3fZD0zkD8jeUGMaoRMDliItOm6y6/GftB1XWdZhkHmLMu0V6d0gCHKncf26Pj+0O/Q8eg8yygBBrExtOit8dctxwN1PDknjFbHG9X3eHT8XGMMOd+IgW1sjETHtzOdtHJzo9PbnkwOw3Auk0c1eg0iI0dRhAGoLveVsiwxcqunwArGPBYNBsp6EpzneZqm8C+1N9lDB2QlUMeT84BMID72xy9OFe0wLV/DXmF64HrBMDXriXhujEGhOtFB9FcONPQKOxWQaON8UuS0GfNzH3Pa1grqeDJ5bLf1VafIQV3XGIuUdK7QwNYVKIOsA/KB6hF2eo3JBiOx9ulg/GeMDlRCCCE21PGEEEIIIYRMD+p4QgghhBBCpgd1PCGEEEIIIdODOp4QQgghhJDpQR1PCCGEEELI9KCOJ4QQQgghZHpQxxNCCCGEEDI9qOMJIYQQQgiZHtTxhBBCCCGETA/qeEIIIYQQQqYHdTwhhBBCCCHTgzqeEEIIIYSQ6UEdTwghhBBCyPSgjieEEEIIIWR6UMcTQgghhBAyPajjCSGEEEIImR7U8YQQQgghhEwP6nhCCFkaWZZ5nlcUxZCdm6YJgiAMw9NO1WhZKLtWQpZlaZquOhVt27ZVVUVRVNf1qhNCCBkR1PGEENL6vu+5CMMwTdPh4ul86PgsyyRDoGJPScuOXMdHURRFEX5XVWWUjSzLzjg9eC5VVZ3xdQkho4U6nhBC2nYm1ES3YU0cxxBteZ6vMG1nSRRFvu+Ltk6SxPO8OI7P5upFUYxE1kdRlCSJsRIdD3v9mVEUhe/7tMoTQgB1PCGEtG3bNk3jFKxFUayPlC/LUmzwQpqmZ6bjwzAcg47P8zwIAns9CsNqPW2SJBnhGA4hZCVQxxNCSNt26/i2bdM09TzPKezOGdCpRiY0TXM2Fmjk8xh0fBAETrE+Bh1f1/VIcokQsnKo4wkhpG17dTyUk+d5ZVliT/G30X7STdOkaSpOKfqveJxrv508z6MoEttqlmVRFMVxXBRFEAToOYhcS9M0DMMsy+DagVNp/4qiKKIoErd+OXBuMoxMkB2appH1uEe5NHIJOQawc57ncRz7vq+zCOMYOtnY2cgunaVap0LcA92dkOzCBFBkF3zH5VR6/7quZb3v+z3e7RDreNbOTVrHy33pwlPXNW5Nu2bpoiVpNp6yFIm6rrGD9nESgiDoeoKEkLWCOp4QQtq2V8e3bQthDfEXhmEQBBCjEFvQfGEYag0qQi2KIqyB5sNJxF0HOl7kYBAE2KGqqiAI4AwtWlAEep7ncqz8xYF1XSMlEND9ybDRwtQ2PONCkkuYqgsdD58cSM80TZumka3onMjJcVoju1rXtNcwDCFqZauRXZiI3M48goIgSJIE++PGcba6rn3fF+2LTV2DDJgSoLsxgqHj0cfA09e5KrOE4zhGYnBOXBGdJSQGWeT7vtyC3IWxVYPOkjPxhJC1gjqeEELadp6Oh+iEgAuCQHYzpCfkmmFLlr+YSisqEGZ+0eKQcToBEM2QdLb4xrUg1oMg0G4/OBXs4nOTYVNVlYhs46JIs04kNLGoXt/3tcR0XloON7LLyEz81dMScC0t3HVKkGZJic4xdIRk+EI6GE7vlDAMu1SyoeOTJJFsN3IVSdWxZXDFuq6Rh5KrSJuMUegiYWw1cpWBawgh1PGEENK2i9jjAXwnDKVryNZ+FWuINmOr7AClaOt4aMokSQwbuU4wRHB/MrrAXE+x5XflkiE0F9LxxlZDx+PqWq3iTpEh9l106XjoZkOaawO5gdMEDrr849M0lZEHnS068bhZ3S0pikJGWrBnl443JPvI43USQs4M6nhCCGnbBf3joyjCVEhDXi9Xx7dt6/t+l47H/kmSYJNxIOzB2H+4jq+qygjLIx4sWH+WOh7eKVrCyjiD8y66dDz2NKS5M9PAQjoet5CmqTFF2NbfengBIx5RFGVZpvekjieELAR1PCGEtO2AeDVQV8bHm85Ax8MWbut4iNosy7SVWtCO+wvp+K6g6RCvZ2+P1/0K3DIyZFF7vKf8apz5qc/Tr+PlKMTax2mN9HTp+LIscReSz8fQ8fSrIYQA6nhCCGnbAfHjoYkNJbd0Ha/jkOhr2bpTxJwEmdEGWu0xv5COtz8zhH6CtsfrRBqu50vU8br7pFMi84AH6vj26PQGAL8apxS257liZnN7NJSNUWCcOl4HvZGTGCr8GDo+SRLOcyWEtNTxhBACbF0oQQN17D/DJCzuK1ovGlMY5a8RZAaiUELfIAGimBF2RhQzVKmEVsR3PUWYikleh3YREdmfDDsTJGZOO/MA0TtDqUsYFpkRm+e5eLCICNYzU/Ut46+RXSLTq6qy9bczQyRh9tRVyGU8UMSrka3Iva6IPXbcSRyLp6z7MPB6quta4mzGcZznuYQYkiCbuouixzdkEgJuWfJfMhA5YLjQMO4kIQRQxxNCyP8PFGgQRZE9qRH2Wk/5XodhaMR4Qbh3/VfHc0THQF+oaRrpSEikSCNcuj6tLUPzPJcrRlEkFtz+ZBi3Bv94eNfoo/Q+EMHeLIA9EpxlmXFHMO3L3ziO9aWhVo1LNE2D1MqN4xNUklpj3EPWSxdInouORg+tr0O2h2HY/3Ve4ztQ6GDgLrSdXq+v6xqO9Tiz9J2QCUZEfwl4n+c5sgVRQY0ioTNQ7p3fgSKECNTxhBAyCvrDyPQHfSfLJc9zPapwDJz+MEsBfbmln5YQMkWo4wkhZBRQx48KjDOc5PDT0PFlWdoTGAghawt1PCGEjAK4VXSZWuFJ0vUJUnIaRFEkDu6Loj+puywwSsAwNYQQgTqeEEJWj3b49qzvd2ofd/pUnCVZlvV8+NYJYs4Yrv8nB/79tMQTQjTU8YQQQgghhEwP6nhCCCGEEEKmB3U8IYQQQggh04M6nhBCCCGEkOlBHU8IIYQQQsj0OCMd7/3R48KFCxcuXLhw4cKFS/+ygMA+Pe1+5DKrzhEuXLhw4cKFCxcuXMa/LCCwT0+7E0IIIYQQQk4J6nhCCCGEEEKmB3U8IYQQQggh04M6nhBCCCGEkOlBHU8IIYQQQsj0oI4nhBBCCCFkelDHE0IIIYQQMj2o4wkhhBBCzj9N06w6CWTJUMcTQgghhJwFaZpGUSR6Ok3TOI7rusbfsiyPfWY5iSbPc63dkyQJgkD2zLKsqirn2YqiSJLEOGee51mWLZqwPM/DMCyKYtED27YNwzBJkmMcuD5QxxNCCCGEnAr1UZIkgXC3/2ZZ5nmeCOWmafSBcRzHcVyWZe4iyzLf922RXRSFXo/LScJ83w+CwGmkr6rK8zxDfDdN4/v+EGEdx7Ecm+e553nObkZ/XtV1HQQBuhNGPsw91fpAHU/GSBRFvu9zBLCHqqq0Uee0ybKMRpFJkGVZmqYruXSSJMew1RFyjoHuTBRhGMLG7PwLIHnLssyyLM/zIAiiKIJeL8uyqioo2jzPfd+Xv3VdO1uENE1FkeP8WB9FUc8LW9e1U3yjs9EvytEHiKIIfwfqePRqcMuCvnfNkF7BmjAiHY+iBuyhpTAMZavv+7K+aZo0TX3fl01pmuqiLJuA7sY1TaM36X5nHMdhGHalwe6/GqeK4xgFtwdcwl5v38LAmy2KQk5iv5w6e7FDf/JWq6Gp4/uBiaUoCqPgoXAOLwbD96yqCiV2fR6KsxIYOVEUoXfX83zyozWNAAAgAElEQVTjOLbfdHQLsSaKoqIo8jzvGnB3Guratq3rOooimsoI6UEr6faogbwL2KTt9XEci1buAUZ0CF+5epZlUi1AQBtHden4oih0gjFEYOyDwQE51qnju5qSfnu87epDRqTjAdoYXQI06HrKXyjXKIpkZVEUYRjau0H75nlun1NaPlmDVgraxdgZDZXnec4GvizLIAjwO8sy/YJBsstVZCteFTlb0zTIAfv8A29WBHrXzeoWXXfT9e13DbStkK6+zZnRNM1IbI1lWRovSFmWUPCyZngxWLTATE7aHo+eSmC0RFGkG2PUGF0SIQgCefFRfqS+QsXSc++oo7rObCSDEALgjJ5lWVmWIkyLoqiqCuK4S6E6dTzUeZfTObzwDYIggCNNFEVhGMr6MAyDIMA4Hsz8cNSBCQC9hTiO0zTNLJIksQcAwzDUvkM4lR43gCqzOwCQWHpowvd9Y7xiJA3xeBidjm9nFnSnlNQ2WrRStqpomgaFVTdCEKxdSsV4edI0hVHTOTwtDbzdD66qStKTZZk+raHj27ZFKwjLmXEX2FkX1oVuVuxt9kuiXdbamYazK4I0TUfV5UWFtVodn6bpqtwVDMIwNCoylEmjeAwvBsP3xNVHkg+nSn8lMEIwAK3XoFR0pT8MQ6k0YJvQ7xfeOKeOlzqn65WE0+3x5rQRco6BVhaVjJocfzHS3jXJ1anjYfMebmjA/lDtSEZXk1oURV3XqEBEfA+/TViatPJGDZNYDKldnffuHEBYW0aq47ts0rrlQCvrLPeQp/pwNEv2CdH502ukATMMnALM1ZDaRknSOt54u2wdj5Q7dTx6HbqIL3SzmAXiHNYYqOPHhq0zzhj0o8Yg6VAXG1nRpeMHFoPhe7ZtC4/MsQ3XLJe5lcAIEXOaMFzHO63vaZo6JQI6tEmSeC53LACv3+PcBiHnlyAIxJiIoXj4eYsTvLF/VVXaRxyRbWQrRuMHylk0HGVZiv+9mLqzLOvqkBvOMFr6I9nOaxmOQ+0w/3hY/TWhwt5k13hry0h1fNM0kG6GyBYBgWKhHeU1KH+G8IVSMaQweqV6jcwSQwJsEz7EOty2jJZM63gDW8eDHnu8Mdd7+M1Ce6EzYAxrDNHxp/FuwI8ojmNxww2CACpBjMHy5ldVBZXQNE3TNMYsAtwOJg9hjZ6Mr3fGYKVxoPYD1q4FeZ6jdhDXKbEpGnMJoG+QvbIzyklXqnASWEHEaQHXkh3kVCj2XVUeajRjZZeOH1gMhu/Zzsrb+R7Z7K8EME0lCAJpffHIEFxCHqI+CmHXsN7OOjSxRpmZW2A0KOdG5TZcx+PR+76v04zhfvtAlBDblUuDKuskEfQIOX9Ax8NBBQZ4VDXwFbHfJi3xZa4nKgFUKThhj2UdoL7C66xFNtQ83n2nFzHauKZpUDMgGXCnieO4yzHGdqYYHq9GgONNHMfaG7nH9WidGa+Ox+itYfMWHY+Gp8fkg3ZRN5loeAyfTvvNkeIu/ujGDv+vvTO4cpVntihpEQdJEAOjf04EREACBEAAzBkzZ8pYb3Ce66uWBMZu29303Xt53dUXgxAySEelqsLEugr0A/b3dfw0TdIBfvR99GJNe6Wu/Hd1fLpA8X1MB5tLhokAi1lRVaPATWsuiWNvCdD6oP5ra3b+dPathK+OlZ1VX5l7QHA/pS3h+W/DV0nkaygHJEm6g1pZC2jPkHgke1cE9V9ZhaSONVVmBzo+nLgNzu8p/GX+SY47AT/d0rNvt1x08+iu84s5Ws3T4eqLtOjsS9YweXzDRNi81288r+P9bFlBrnsto6HUStgT6zr1357sATyKt8d3XVdVlXWwWXu8P9ALIfUwiseTsvePs2eeZzmX+3T10YOpEWcvztWSXUbV2Ktw13Wp9fMhHa9QAZ1U7j2a/Gjac6GApY/xe3V8uIkbPx58R8eHZPl4HMfo3o0CsTXiRveNF+tmKdc+T+t4TzrjfFrH23ntorI6PuIdC+LpJCoN/PWXoJbf0/H6r7WSTfns0iRrUg+8yJbsi00XRvy3qSRKXRGOa5V65nhHL1lo7CvVP+0NVUgqj451fLh3G5zf0/bZWx36A5zpBNI0z9mbx684Rbe69RjeSUn3p0bH4xsmIvuLnNfxwmco8vH0e0fpQrLRrmoQEtcAeEzHa4F6XVdpcVkEzut4C9ayAtOwUWUYi0LdtOycPtrLsvhZvd4AJV3h+/+7On5d12yHE+l4mQv3ZL3icWUWUdKwuq6VPoslviy/WscHZyjVzfSojo+UkG4mb0+KbovolWOpn3pIxLoGM70g7Zv2eFUvLeHRi/Xay9SkruKuPV5uJ3snehpJivM6PvrWKyFpnUi1mHCPyt+7Fmk13Vrqv46l2J6OjxTYQa2yssz2j7KjirRD1B3yhI4/vg3O7yl+PFzhrZzpBB7S8boNbNDyx+6lf9VQenDDRPi1I+NRHR9cviwRdY/y8PE7H0S7Hsw6AP5NtLwmi7hlbpHPetavxh+ocUQZ5W1ciwz8PsBpnuf0wdyLiJvn2UZn0yHqgrzaPqPj9UeULceGY+/dvjc6m2VNV+pVnIr9/RF9H+a36/hwu/Nk8z7pH29G7nSgMuuaFrj9V5aIJiLdLZsYRLOCb/rVpHr0iYuNtJfarbglkPoR//gX6ngVFbVGahpUH5QGburnk5OfF1vf1PF3a3Ugy3TqM04IT+v4cHgbnN/Tt8yf1PEnO4GHdLw8r7zzjN2W8pHN1uRVOn4vDM4/GtEjb17+0VV7ie/J3rroeIAIMzMrEDzK6HJgQVNqDQ1b3pIdBc6WZalnWQ66KVVVWVEHYaN6otM4V3PzC/ccgSIe8quRF42cjiy3jzVUGpcIF9Dx4WYS8y6n4abIszOzPcN2uA3AFlniv2rbNr05zG/btmSN7jbsfT/OVXtGKwkPXWyqvSzc00d2hg/mq3m5PT7qFFJdpQ5OYiJa3jFl80Idf7dWd+3xZ0TP0341/vD0Nji/p137X/WrOdkJPKTjg8vIXnx1WTl4AB/S8dlfRLXaEwd+/2z0WOTblho+wu2BSm9d/GoAUuZ5VgxYuJmWj6Wt1uXMNVwR9pGwjuLpj93HJcSnaTqjg7M63k73Jh2v2YgM/7ZMIRu8rWC0595+9e9wDR0fnCnIvtoT64rZSg2x9m15w59FNrN0/zRxe1bHW6DY93W83ceRW9v5i83aUG0F/6SOf+0Y/EIdb9+mDuU+H7ZcAtRu9sxrQugXLl6l4+/W6liWWXYm716fdrXPxbl6srfB+T3FwZLopTnfCTyk4w+W6aSD09RG4UEdn41zDTd9n11eb7++kTE128t050+RHfvrr8m1xL+Q1AjgIfQ4eO+Xxr22XLk92q/vRrVoJe2f5nGPdPwxPmXwmbcpRTpe//XhhZV76+Xx8uxD9nib5+i/5swzDIM1zp9cDX6aX6fjN/cC4YhUOZlK8/eWVogOZqUa8/wwJjWcVa5mZ7W7apqmvVwiB1bVbLRcuCmwqEBzpPFP2vmLVVDI3oWnvr/RzlpVf613zfA1yX0amaqatLd3Y8mvwx5aE8QKV7cAaJ/gxUevelHiXZVsNSbcuiFfbPE166IXKBa5H25vlk1/0ONaRVl0tHMa0u3ZCzRMNXQ2CeD52+D8nuHvSrSHOgHJdPuvyfHo5rGRu0iwHzH9VnU4vmEisnknw81Fynv8y5oVmQna2/tZvaeN7xl8bG6E6p+1OxCUBiDk6BJuaWq0URmWg3urkd6gZL2r7PcHxZ7X8epAfL+tnDAH2jrS8cqEa996HX93YeHRvJNagtC1m45X37U3Wv3L/C4db0vPRc4dXOIpGsYUH21HVSdeDSDFZo9H5BHry/fZx1PSIT9reIucSv11+estvtreLLedr+rdi/XfZsddixE5vrS9Mfs5fK3K2+t1DPNTt4vy36q25rHtU3xaE/kH24pSh+VPLQcb84Aab++dVpv4k9pEwhelkpXCMqq/XeleraJqRC1gJn+f0HCv+x6+vgcqzXdU1/X52+D8nsaffA/U+U5Astj+Kz+cqA39zaO3DWTjmKM5nu0fzt0wEXtdn6WI9qdIHRfDbZzWPv53949ndIqoB7Mr4j1QAIY6bZvVp3ZA5YfR3/ZmkjMln9TxkVHJkFzWemz0MpNw6xVtKSAysHodf2w5Dfs6Plp/CDczok+UGeXqUWN6d1n4XToeAO5S39Lw/4NnvyJZb9Th9qqpV/F75leaBpNTAkDIFV7PpmRo9xU52FhY/Pme4a6Ot4DXvcUx9RuyUNh5NQ+3iERp60ipy8Ah77vituKtPfdCbLMba/d6O6XFtIT62sFXzHYrcnmZ/1nQ8QAXQ/bdH3FaiJZW4S6yY6Xyepqml/+CvyT8q7m9DwsAIrQ+lvKcp+KeY4wmAyr27tK6YrGi7kgePvM8j+OYruDZPson85JJu4qKNqpPS68RM4EHHQ9wPbRO+mGDRN/3rGY+iqxWbdv60XQYhjf9drJy/dRvJL810tQA/AEsAPenKwJ3QMcDXBKtYH6sk1UG38+c64+hpW1zIj8IfngJL/fYOc/TZkUAAHgOdDwAAAAAwPVAxwMAAAAAXA90PAAAAADA9UDHAwAAAABcD3Q8AAAAAMD1QMcDAAAAAFwPdDwAAAAAwPVAxwMAAAAAXA90PAAAAADA9UDHAwAAAABcD3Q8AAAAAMD1QMcDAAAAAFwPdDwAAAAAwPVAxwMAAAAAXA90PAAAAADA9UDHAwAAAABcD3Q8AMBHWZal67qiKLZt05ZhGOq67vv+HedqmsZO9LN0XTcMw0/XAgDg7/CLdHzf98WNeZ6jb+u6tm/LsrTt27b1fV+WpX3V970ftOwr0batP9Z/NU2TfdW2bV3XvgIadw8YhiG7va7rvaHruPLPNQgAvIS0E3gJvtvRw25P+st1/DRNZVlaz9a2re+aPt9vrOvaNI3vhAEA4Dv8Ih0vNNKUZbmua/ptWZbLsth/p2kqiqJpGts4TVNd1+lu0srjOKZlNk0T2auWZdE45wtp29ZGWY3EfoxvmkZifRxHPx7LGFYURdd10XlPVv6hBgGAl5DtBO6ybdtJe3NVVYWzx0f9xkuY5znbb+jU2f7kMzRNk/aHAADwBL9Ox4ebBb2qqnQtuCxL2ygdnBrMtm2rqioSuLJ47en4aEjr+15DnR9W/d+pjl/XVTuoVtHOuqJ0BnKy8icbBABeRbYTOHPUyf21nhb1Zq/V8XsrgdGpP8+6rn6VAAAAnuaX6ngZoVOZ62WrRtnU4SSEIBcXf7jEdFqg1nn9Fu0pa1xVVbbdnyjV8bZDdjzWwOnHrYcqf7JBAOAl7HUCxzykxd+t44dh2OscflzHhxC6rnuHzxIAwL/GL9Xx27bJHSUS2TYyaRl6z79zXdfUrVxSOJLOfd9HRvphGDSaqgJZE35Wx4t0PJbxyY+pj1b+TIMAwKu42wlYMMw4jtozCo+xHkB6Ws+7t47f1fG+wMihXF1ZVVXLsuxJ/7quo75i79Tbtnm/eavkMAzyZZ+mSXaHqqq8MWIcR21Xv6RVTYv5mabJrj2tifrArCEDAADO83t1vDxMIs9yk63ykzmw6Gj88APnPM/piJga2zQ6Bue/nhZ+XscPw6Cr8OPfo5U/0yAA8CqOOwHFsZhBwSbkst97Yd11nR2rKYE91Mc6Xl2EZK4EvR3Y9711Yl3XZWNGZQs4kPj+1HVdm8+eKjnPs80iqqrSqZdlkcuf9LoqrK/UtepKVYL+q04vqr9vK3LXAAB8k9+r48PNkp0q2vCUjg+3Acxcz8dxjMKtpmny46J0cxrodlfHZy1zxnM6/rhBAOAl3O0E+r73D6/1IZGOX5bFP57S1mY4ONbxXdfZnlGxUXrKrFj3IjslOnVVVXa90tzS36nhQ0Z0Xa/+tmbxXovq38xykU5vwq0LJXENAMA3+dU6PtzGEhsVHtXx0YK4xh4bPOq6jhZ267pODefpSHnSHq9UlWlmhkcrf6ZBAOAl3O0ELIIla2P2a3FFDj2wJ/3jLdzWei35wDRNk3X5E+roTup4oUh91dAM8EUuUW+0hin3m8I5CmZ1fCrZswFLAADwEL9dx4fbcKiws5P+8ZahOTWlm3VNy8T+K8s0F5H63pz3q9GQmZ1OnK/8mQYBgO9zshPwb5MwuRzpeLmJ753oro63+YO+Mh1soTJF4rBuPKTjVWBVVX3fex+YrP4uy9KaQj5FcqBXCJCvOToeAOADXEDHh9vAIO/MKF/NwTCWHSQ0UPV9n75ZsG3bdOTTkBmd5byOtyDXKLXlQ5U/2SAA8E0e6gSyBuzIHr+XXfFYxzdNY51GVgcvy2LBqam14q5fjWluRd1Yb3NGx8sPXnv6NcOHdDx+NQAAL+EaOj64NxFGWV+yKdg1UGVfdKKMclECmRDCuq7ZBHPZRO8P5atRPaNQuYcqf7JBAOA7nOwEhmHwXu9lWcp3LtLxcoGL0tSciXONNG6kg72fnrqR1MEmjXP1yt6nsokUf6rjfccVFeJXGx7V8aohca4AAN/k1+l46eysBE/dOk0i+9BVpV84eAuj1sQjv8+6rg8yP0SD4kFiaQ2EkU+8zljXtR9xT1b+oQYBgOc43wkozlUPqXzbpEe1m0rwETIefWvvhjOxG8XMyH1lXVdLCtm27TiO67pKheupV2+T7euivJPaU3lpqqqyuCCfasZePj0MwzAM5mKkXstOrQP9GoV5+q3rqihhr9GzNgvyTgIAvITfpeMlTEXqWqoR6CA8SwPV3XepaHyKzEWGLz9KPqMqaQCOBubg/NoNO4WljIxOcbfyTzQIADzKQ52ANK4Fd3qjsgWhWgk+2lVPd3SuYRh8+nY95pK56l60SlCWpfS0PObVM0QhuZ7oPVDmVV9VVWS/t8mGaXfNUsyObu743jyh+KLiZonQJWiG46/XX77vwXgPFADAS/hdOh4AAF5ClKHyUfbiU7+PliP2ZiAAAHAedDwAwB9EPj9P+668T8c3TZNm4wUAgCdAxwMA/E2UEfIg0/zxscXhay6eQO49pKkBAHgV6HgAgD/Luq7eX/8kPm6neF0wfZrtFwAAvgM6HgAAAADgeqDjAQAAAACuBzoeAAAAAOB6oOMBAAAAAK4HOh4AAAAA4Hqg4wEAAAAArgc6HgAAAADgeqDjAQAAAACuBzoeAAAAAOB6oOMBAAAAAK4HOh4AAAAA4Hqg4wEAAAAArgc6HgAAAADgeqDjAQAAAACuBzoeAAAAAOB6oOMBAAAAAK4HOh4A4CdZ17Xv+7Isp2n66bq8nnEc27b96Vq8ka7rhmH46VoAwD8KOh4AIJRlWRRFURRlWW7btrdbXdfFjYPdHqKqKhV4RsdbPYUk8jRNfmNd19FR4zg2TWM7NE0zjuM8z0/MHNq2Tcvfo+/7uq7XdfUbt23TvMUavO97bXy0Mr+BdV2bpvnbcxUA+LWg4wEAQnBqeE9QLstyXnA/RNd154td17Uoiqqq0ro1TbMsi9++bZsUfNd1NvGYpkkbx3F8qJ7WAtFZsgzDkJ1RaKbhTy1ZH13RtWiapuu6n64FAPxzoOMBAEIIYVmWqqrKstwzycsUfVLFPkTf9+d1/LZtkdFdYj3r3aEKZ/X63iHH9dTqwV3b+bquZVlGDWUiPt1/nueyLB+qzK9C1/snPaMA4DeDjgcACCGEZVnqupakTnWqVL6+/VU6XtXOVmkYBvO9yZbzkI7ftk3SPF0NSEndb7Zt0xxgr/XkXXO+Pr+NruvOexwBALwEdDwAQAg3QSyvldQk37btMAypjpd7tPmdyxdc3t5VVU3TJJ8Zc7pQCZLCZib3Ot58V/aUvdfxwzA0TbMnf+WDPs/z3Wvftq1tWztvVt/r8kMId31ypPijQjSpaJrmbmXCI626LIv9KDqFtfY0TZo5VFVlP9myLFayitJ2hRDoBtAOZl/3v4jFRdi5bJqk1YYzrQ0A8CrQ8QAAIdx0fAhBitbLUBnjw01wmyj03hTTNJmTt4XDtm3r4yDrujYhq30k+yJ7/LHHi3R8VVVN01RVtSfi53n2uvOYuq6tKKnYVI+aGlYgwYEil6KNJiEq9kww60OtavGybduqejqRtaHaQb+sJhiqudYH5MxjbVVVleYA/ltVSVMCH7Pb9733iZfcJ3cNAHwSdDwAQAhOx6euIzLGh0THt23rhamMxDJUa0+v6oZh8C7gUqhSq6bjpReP/Xa8jtcfUUIYO11Wx+twj2YpZlfWgZEKn6bJ++fc9ZBJv5XgTnW8LVCYHH+oVcNNuNvpNM3wJSjmIdxChO1wTdjUPmnUgf92r1jf8iqBxDUA8EnQ8QAAITgdH76a5KWttT1SqFEWSCGpl7q8y20je2rt3HVdWZZ3HTO84lQ9s9Lf0u9kVb6+jeqjTPY6KtLKdV37a9mLIhBS3lGVZE3fS+qib3WKh1rVGuGMjveXb35EOnBPx/urqOvaHK6GYUgle1mWuMgDwCdBxwMAhPBVx3uTfN/3Jmq9jpfy2/OjSBWnfFcOdjaHkON6RopTojlNliLbc7HjyK4LNCWqjDcK5JU9PnIrSoV1sR/tmtXx2rh3iInmR1s1PKjj9SvL68YfeEbH+5KjiY2dCB0PAJ8EHQ8AEMJXHR+cSd5Lz9Qef2xij3R8qkGjnaWhjzORp4rTXGiyAjdbQ6/j5Qtuu6U63tyKPJp1HFxOpONtMpCdV3jR/FCrhkd0vPzgrXkf1fHhZpKf5zmdkOBXAwCfBx0PABBCouPNL8VL2EihmgXdfFcsmWOqOLXF50jRxmhnlXk3zjVSuiblvUq2VI/pxMDreF2pnTHS8d6tyJP1zBHZOFcrOXIrF140P9Sq4REdn4Y3PKrjVXiajSckzvcAAB8AHQ8AEMItTaHf4v2hhbSd6UhlVom8TbwY9arOVLVHRclUb9LzOLFj9n2uwbmV+1e3ruuqwpumsQK3bZOXi3S8rNTy57G0jMMwDMOwbVtd11kbs/ntpF7y2byTwuYbPlv8OI7+BVsPtWq4Bd3aj6JTmCJXZQqXmFIVHsfRonWHYTBPKqvV3vpJelfYVRTknQSAz4KOBwD4EltpsnWaJhOpJkANKTmfj7xpGq/Lo9LCzQ1d2+u6lh6NTu2d0bORlL4OtsOe8LXK23mtql4NS9ZLIqsCerdUer3WMv6r9FWs6XugDEXT+gqXZdn3va/wyVaNcu+Yy7sVG13CNE2W5GccR0tpH12OSX8r1tc/G+EaeA8UAPwE6HgAAHgxPgf8H6OqqtToLun/J68XAH4z6HgAAHg9ChE+8xaqCzEMQ9bo3jTNcXQyAMA7QMcDAMBbkOo9fq3VJfAvq4qM8fKVIk0NAPwI6HgAAHgX0YtgL4o86aNcQ6LrOnLUAMBPgY4HAAAAALge6HgAAAAAgOuBjgcAAAAAuB7oeAAAAACA64GOBwAAAAC4Huh4AAAAAIDrgY4HAAAAALge6HgAAAAAgOuBjgcAAAAAuB7oeAAAAACA64GOBwAAAAC4Huh4AAAAAIDrgY4HAAAAALge6HgAAAAAgOuBjgcAAAAAuB7oeAAAAACA64GOBwD4SdZ17fu+LMtpmn66Lp9gHMe2bV9b5jzPRVH0ff/aYiO2bXvHL6UboCiKZVmWZWmaZl3XF5YPAH8YdDwAQCjLsiiKoijKsty2bW+3uq6LGwe7PURVVSrwvDocx9Fq0rathOBLKvNu+r6v69p0qmSrLqRpmmmaxnFcluXRYj+j463NX6vj7d7ThQ/DUJblE40AAP8g6HgAgBBCmKZJcmpPDi7L8g4ZF0Louu58scMwFEUxDIP9tyzLsixfW6V3MAxDXdf2X4nvpmn032maJJRfImG3bbMmeiEP/VLn0WTGLnyaprIsscoDwF3Q8QAAIYSwLEtVVdLEWVt727YvFJoeuVWcVIdlWXo1HG6y77VVejnrukZmZolX39Tbtr3KFN33/TvM8w/9Uudp2za6r7qui35lAIAUdDwAQAghLMtS17WEWioBpfLNj/m1pz6vDrdtK4qiqqpou1m1fy2aBfkt2UlR3/ffb14trVxax6/r+o4TAcAfAx0PABDCTcdLP6Um+bZth2FIdfy6rt7DW74QCoisqmqaJnlidF2n/VWCtPg4jn6jRJt57+zJOMnfuq59NSIfEjnb6EK8B07TNH3fj+OoEmy7+ej7IMtlWVT5bdv0h/fnOT42Qob26FhddVmW1g4hhGmaFO5pjdD3vWYvwqqtC9R/5bEj4S6/I3+4L80zz/Ojv2Ck47dtkwSPGudk02l727apjg8hVFX1+6dnAPCzoOMBAEK46fhwM4561SVjfLjJONNb8hWRqpNzi3aLglCbplGGlrquTZlpH0nJSB02TXPg270si0VGqvxoh67r7CxSqDYDkVSd51kiVTtHl2Ce2elZVJrqfHxshGYO0bRk2zZrKAW5+m/Xda2qypvwdQl2dknk4KZGZoCXcLf/KnzWt499++gvGP1SdV1XVaUpn2+cM01XVZUPbE11fNu2v99dCgB+FnQ8AEAITsdLBXrfFRnjQ6Lj27b1zhsSiJKM2tPLcck1+69UoxShqUOJ17uOJdu2mQlZYtFWD6Ty7b9aXtC1yNvE53zUldpaQbgZiU09S85aafrWrxscHOs58EcyFS417/eJjlL97YzDMJg61zxhT8d7tKfNcx76BUOi46uqsvb0jXPcdLoQP2/RmkbqYrTXaAAAAh0PABCC0/Hhq0le2lrbI2llZlePdGHqSN00zV7konaWedtMtmcqbGrerMKRV4mxbVvqNS7Z6qWqdH9RFLIiZ8Wo9r97rEc770nSyDvFWiCS47JP22/hJyTRpe3peFnfra3Cg7/g3kZLAO8b5KDpUkN71q8mmhgAAKSg4wEAQviq471Jvu97E2dex8tpe88BJhV88sE42Fmi/K5LdCRPp2mSNdecTPacMVIdn3oQhZu01TUei5CWo7kAACAASURBVNHjYz1ZHR9diPmp+1ayRtu2raoqk7baee/S9nS892UKj/+C6UYtjCgAOsoHetB0dV2j4wHgJaDjAQBC+Krjg9OpXlam9vhjE3uk4/dkme0s6eadVVLSM0q2WsTn3ln27PHR6Xw2+rv2+INj0wtM/b9Ty73mJNEZ5dA/DIPiZdu2Hccxio69q+PTBYTw4C8YbdTUwocLn9fx0apFVsfjVwMAd0HHAwCEkOh4ey2UV36RtDILumkye/1QqgK1RSlQ/MZoZ4tM3atnlOAl3BxaJKn1cqUoOYz+TnW8tqT+9OayciBG7x7ryca5tm2bzliqqvITJ7s0O1HTNGVZRrlx7up41Tyt20O/YLRRJ/XpgE7q+HRGIR0fuVTpqtPGBAAw0PEAACHcHFT8Fvk/+ASU0lum7eRvHXlXS+Wnclzm22hnFSXNZ7pTx0Zi3dAZbWe5dvhEMZbo0JB+zWpZ7ezz23j3cVXYZ1nxpz4+1pPNO6nG9FZ5qeTowtUadtIoUNUfaBv9jKLve81tIrv7MAzLsjz0C4avv5R/H63FKgzDoEMOms7uBF2pIp7TSSN5JwHgLuh4AIAv8Y6mdKdpMvmYxo9KsPpgU0ueaFkLI93s88zUdS3RFp3aJzvP2raVT11+8LZb5KDia+tN/iKy8lrew6Iouq7TdfmU7UVRTNPkQ1F9kpb02Czpe6As3ftB9slwE+7+AqMpgb+0KFK5aZrs9ElIr5//BdObxOeGN++mKF19tul80vphGNq2jZKN8h4oADgDOh4AAN6Oz9QOd+n7fs9xHwDAQMcDAMAnUNDwgc0exDzPe2/UAgDwoOMBAOBDyIuGHCwHjONYliVNBABnQMcDAMDnkL/4T9filyJnfSzxAHASdDwAAAAAwPVAxwMAAAAAXA90PAAAAADA9UDHAwAAAABcD3Q8AAAAAMD1+JCOL/5X8OHDhw8fPnz48OHD5/jzgMB+n3b/cpqfbhE+fPjw4cOHDx8+fH7/5wGB/T7tDgAAAAAAbwIdDwAAAABwPdDxAAAAAADXAx0PAAAAAHA90PEAAAAAANcDHQ8AAAAAcD3Q8QAAAAAA1wMdDwAAAPBLWdc1u33btkeLeuKQa/HnLzAFHQ8AAADwOfq+31Pn2Z3ruo7237atqqphGB46b9d1TdOcP7Vnmqa2bZdlCSGM43iw5ziOTdNoT8+6ricrvFeClVPXdbb8uq6P6zZN03OX/2tBxwMAAAB8iG3byrJMpfnBziZ/13Wd5zmEMI5jVVVWwp5E3rbNC/eu66qqeq7ay7IURdH3fQih7/uD+cA4jkVRRDp7WZaqqsqyVP2zmMjW1e3ttq5rURTZs+vU0zTtHasW+EtSHh0Pf42u64qiKIriYDZ/zDzP1luFEPq+f8LsEUIYhsEKeTfLsjxtZYEL8cmb6kdomuZgDAb4AwzDUNf1yZ01ADU36rqWKbqqKv1t26uqSp+dYRj8cPYdHS/1LGu3Zhd7fZHEtMajZVnGcdQlD8Mgi/66ruu6tm0bafq2bTW9eUjHr1/R0L+uqw2L3gbfdV3Xdc+1wO/kF+n4vu+LG+l0ra5r+1YT2WIf3VtlWUbbdYtv2+Y3tm2bVkbzTnsk9CR4vED0NfcPZ1SIMU1TttpN0xyvB8FdmqbRIzqOY1mWzz2uXse3batf51Edr741fL110188Omrv3qiqKnL7S2/jYRjKsnxu6gJpd2G/0RNTuDdhN5VHC9BRNzLP80XV8DRNz02bAa7Cnk9IuueyLHVdb9u2bZsEruj7XjJpnudj67Ikvv03q+NTn3KdJd1Y3HR8CEF1GIYhFWym46XITQiphL7vx3GUUvdjtOYG4zhqbUHXJbmvDmEcR2uE4qbjJdy7r2jgbtu267phGLquK8tS+6Pj345a31o8wssUW5mK9um6zuaIulE0vEUFNk2Tnbz6akQSX4Nldhot+RWp8Gwhvp5e5VtVkfJPI/19sGb3HJrFPSQsbDphSCbaTSixUhRFtkOR0UJ/q5Pau/HUidt/p2nae3bgLhobfDtr2Nj7mT5MelNpxVzVs5F4miZtvG5Psq5rVVXXrT9ASl3XJjGlXyO884yQhLX+XPZs/0e0PcV8cmwCYF4lhilmf+A8z2VZNgllWfrFAekocxCSYpYLvvol2ez92Ocf7egxV98lia9ViNERnLNN6lezrqufjagO/r/WeaLjP4EUT2qA1Fd+Y1bHb9vm13rWdVWB0Y+aLd9KkBdXdDo9Etm1nnme0yE2W4ihm9tPJDQZeHrNCyS4X26QflTHZxcEdRP6O8EWedKSI98JLexk7fey1vgtXdedX7EFj5Y4otbTU/+O+eFDZG8qzTGyevdXLSM8gdbT/sHUE/BX0SpTZGmWppQHSNrJmM7Wf21oi9xy5EMSQlBRvgSdy88W6rrWSnVEOoUoct4EkQU9Yts2q7PGYru0MzreT1qyPd6Bjp+mqe97We6jyIGAjv88ZVnKkp3KkTM6PkVmWhNM6W8c0fd93/eyl0c3dyq+Rdd10RN4UMheUeYpwej1HGrSH9fxVVWlXoNZHS/zRirFUh0vm0dqGE51/F7/C3fJ6vhwk8s/K4vTm0q35d5y37Ztl9bxYec5Argoplm9QjVNuRe4qWFiOIHERjRApMlbTvrH79VH6wm+egfBpub3ckbHL8viuyzfSprweKf5vept22bqcRgGG3DR8Z9GYl3rMpEB8q6O3/MK1ZhXluUZxwOZ6qX+ozteM8uoVnJcO1+ISHW8bv2/akzV01VV1bIsfng2NwBduzWIdtOz6v0EfKyCdSipW7lOYcfqV9PvrhUb3QzyKY9+U1k7rJKm4zsXQbs311JNUtttVsf3fW8194ekOl4Ll3LF8Z1dquNDCFr3PPoxIMeejlez2w+k2Cn9auabZ2smfipu96pu1OzduHefe7I31UOrBNM0WZyGjWHjOCqqzPJIaKRs21Y9rQWHRI+ev/+976KPtLaHyE7tF9+toay100AULcqfuTqA388TOl7eBDpq70mf59mM8X3f+yFGkTPR/k/reP0tdxdtMQ+FdDQ0HS8H+jM6XmsCflqiFQyNhvr2ro6XwJMfjrwh1J+g4z+NhhD5pUTzy7s6vuu6Y5f3u4GA3jVZw0/0/Gis9YXoVnuokJDoeP33j6VDMrTgpb/9hF5Pu1pvXVfzE/BBnMqzq0daraTGTM3kkT1enaBaWI+3ugCvpfStL8qiliMdb5FJx9Mtaf2sS1hWxwc3yfQaKNXxwa0seRtGWhPpsDs/CSSkOt60tQ2HGrr0X/Ods53VZflHWCNQ2Lkb9+7zqGLpTWV3wpm1OwsOC86KbxNIDaX6rylsebX6fliHWAm6P+0oq5Jaxsqxy/Hfhh0fwsh2qEJ+1p0J4FU8oeMlxLVRDi2pGb6qKo2n6fw/m9fyIR1vXjcaU5R5xmTYwRNqg+YwDOf9aqJrf8ivRuY5b0rQFtUQHf9p7C4x13Yb2FIdXyQceBREpWXxgeTZlWuNQH5jKr7vFhK+ZrnxA96fxJu3Qwj2d1VV/lnVYG+/smS9nzL5PsjnsrVi/f5t2/pvJYbUa0STqKgoKfXUHh+dKNsByfsw3X6g461uyksQ9nW81c2mo1kd/yb/oj9PlALI8DYtjR92M8g64GNMo3vSpmcHd2N6n0ekN5UJ5eMsRio2Cui3yYZ2zsZy+NNlHxaTDr7m3rCSbQp/r0bFRhHb4eskAeDqPOdXkx5+crvFhkZEOn6e56xvnp4+SxCpCUO4Pf7S7kp56Y+Sb4z6K+sZTvrV6HCbFUR+NYNzik7L1Cpi3/fm5yPjxTzP4zguy3Kg4+VPUVXVdU0Gv1rHB2d2Und/1x5vRqMU2ciL/WQ44bb6bP+V7S0Nt9JAqHtUbiFPFOKHsYN4tb+BWj5KrCkREHUiPmmPmmUvStjMhH5jpCpSTWbvsNiTJiGRIKmOjxLMR/V/QseH2yqBmTP3dLzVR7PHrI7XDrjIP0pqj1+WxfuD+Z31akPTyrZdY5jNx+ymOrgbD+5zkd5UZk3PdmX6NlrDiZimac+P6LyON4Zh0A1sB2Z1vC82SjhmqeWMg6cM4HJ8X8dbukbPno63otq2jdLL+EQ0krDpU+Yd3MMtXtZqMgxDNjucIr60UFDk/OO1vren42XsT/1qulvWyKyOn6ZJ1fCZviMTw4GO157F70hK9hy/XccH53WwLMvT/vHmKGbLPdlT28AckbrN2EjWtm30FJ0sxI+OWnn4wxkDLeChcC7F2ZUK7Tbcsmul+kbtZp7lezpeGmXPmPdNHZ8uBRhP63hZBYpbJvgDHR9u95jsDej4V7Gna2U79wtBMkSZacDreH/zWLzH8d34hI7XMFbsTP79/bwXsHFwvQ/peA29MqD4A+/qeF+yNH3UAgdPGcDleJ+Of6irP+lXE7m1dC4NWt/39vKp6CjLnJPGucrwoWW3Ax1vJ83+fewf7zdG85DOpaFM/Wp0dddVXxfQ8cH5jj+Xr0Zep3bgXvYJLUBHGzXp3Bvq0kPOFxKNjn87yFWYdVPSR5ccNZd0vC3bRfpG030LEDzQ8eHw9vimjj9Y8X/Or0aYg3VkIMka3dVQymOTvTr8ah5lT9ea8dsi120YSHV8uN0DkaPIwd14V8dnb6q9pF7h6/18YNX+vo7Xo2Ej8aM63kzyMrlF1cCvBv4Sb/KrUarH89U4qeOHr6ktvfY191f/Mp+oD/Qy2vbXsK4LMaf/F+p4nWhPx6dt/me4ho4Pzsh9RscrRFp/y8zpbzJzu49msV2SQlVolI121thWJu8lPl9Imq9GZr8/aX9Kl7EUzJr+EN5jPtI3kh2mtu/qePNU8YEvPpj1aR1vCT2yV5rVZGd0vGqiPe/qeLPfZ+3HxLk+wZ6uNUemkIvBSHW87p/y61tdDu7Guzo+e1NlMwGI6H7WHeV300r093V8NMF4VMcH15Gm0051FNd1WgXwfF/HZ+Nch2EobzltznBSxyv7jZzjtZxuHYi5D3hf9qgCkY73O8tbRtUokpR9xzp+WZasz332EL/DNE1ZHxuxLMull69/nY6XtsvezamqK3NvZdJtbf6pZfKOtHAbF704G/ZfIWSr6lEOJrMr+1OfL0QKILr7dY1N0/wxY6qW4XyQu8/9Ys3i499Npvim0C+unsVel2uT+2ilxSZsHpWmY23PaDFE2sKW4fSt/SjHXivHeSezmUwioijbcHv5a7qnLpC8k69CCjUKbrG+YnS5F/XrjLeUi1Hm4/DVS17s3Y3Z+zxi76ayFE8+8sTqHGWF8uh2MjtZ2gi+8pqB2A3pU83oK+8mp95bGV39Q2Rjfzob2TPHMB2Fv8R5HZ/tCg784I8nABEndbziPrWE7s1tllNL27VRDjP+8EhG+2/tQjRViI6KtLvW7X2yy4Or9rkEogpELRDFuZa5t7hciN+l4y3DcTq6hJuw85lM9mjbNsrb4K220bHl7bVTIrqxop0jo6wffh4qJKpwGtdb/C0fmyiNdDQFt/YxrRz9fJHg1g+qDkWmiDR/vKVzSbNM+p9DEe7+ZvB5hHzyDV/O8Swr8opJ79Wotuk800z1B7exSP3jV94D9RSpyPbNbu1pkR4ajUytRvLUR7ga6d24d5+nZGPR7FxWrBUeFWVTDnt2opvQovajjb5ZFLkR7aBi9VCoD+z7PnqIouT60eOz9+rZg0sGuAqKztQDKKu2vEOlJuu6rutaf6sHkD5OJ+1v1fFKsOtlt7cE6YkOt5Vhq4aedxVorvDKZ+/NqWlt9xRzquPXde2+vt/KkhlGV62+yGew8TusjrZt03w1xZVdIX6Xjgf4A4w/+kp5BSH9yKnBeHkWs5+9qd6H7PTpdkXN/r3rhX8QrRg/RHrnKxSqyZHV8bI9pWjmkG70q7ht22b93CIX5XDrlwq3WjjkXq1oHOt4XbuVbJreu0nLfhpFS2pl0ne5qY7Xyx+zFhPZiK/rBIGOB3g9SvX1+fPKE/GhsCd4OVGI2Kv4qZvqrURp9UWUnA4A9vLSaIXwhTNeH15opB7wvgLRt1olzg5DEtxnFPM4jnvRqGvyvjytMfp9pmlKD1dbpc2lREB3q/RrQccDvIVsf/FWZBq5rlHh6nhnkjdFZ37+pnoT5mxWJS9119o9aWoAPH/gqX8hT7fGn2xGdDzAu8hmpHkT8r3GEv+DWFqbtwYnfPKmeh9p9h7/FdEdAAAnQccDAAAAAFwPdDwAAAAAwPVAxwMAAAAAXA90PAAAAADA9UDHAwAAAABcD3Q8AAAAAMD1QMcDAAAAAFwPdDwAAAAAwPVAxwMAAAAAXA90PAAAAADA9UDHAwAAAABcD3Q8AAAAAMD1QMcDAAAAAFwPdDwAAADAH2fbtl9SyPv45dV7B+h4AAAAgHexbdt6gmma2rY9LmpZlqZp1nW9e9JpmpZl8Vu6rovKr+t6GIYzl2BFnTlkHMemaaKzhxDWdT15ur0SrJy6rrPl13U9juNBydM0nWm9C4GOBwAAAHgX8zwPwzB+paqqvu/9lrquy7KcpumgqK7ryrI8o4a3bYs0t2lfGa3XdS2KYp7n6MC+74dh6G8Mw9B1XV3X67ouy1IUxXENQwjjOBZFEensZVmqqirLMj2jYSJb7bO3m2qeleM69UENu66rquovSXl0PPw1uq4riqIoioPZ/DHzPBdF0fe9/tv3fVVVZ/pN9X1PnPGTdF130iICv4Rt29q2vTt2vommaX7q1AB/iXEcfd9bVZW3HC/L0rbtsVvItm1VVR3o4IhhGMqylKCXfpVJXkJ2TyurDl3X6RBfyWEYtBpgDMMgiR9dqensZVl04ZpUtG27LIuObds2upa2bVXaQzo+WtbQ0K9Zh2rrbfC6rpMNeAnQ8fCnaJpGj+g4jmVZPve4eh3ftq1mBXe1b9M0TdNs21Z8xR9opQl1l+prbO4xTdM4jnszEOuX/ca+763MtIuv69q+LctS3dzd1dt/lm3b+r4vy9JarO/7H/S5XNdV08gnbi1Z+LSlbdt1XQ/mmRpB0+3TNJ2cxwLAAW3bqgfWf/VYmRrW8JEeta7rPM/aTVaYrENO9gndtk3b/bnMu+bYppPV8dLiY0I0YJmOlyI3A7n0t61CaF7ha1uW5TiOahBNNiT3VU91aNpoOl4jWvcV9Ydt2+oatYih/dHxAL8X6e/ztoqTDMNwV8fb/EFM06ROJLtzVVVm4FSdm6axAyW89nR8VVV7lVHP5ccJT1mWvsyowiD0w/mVHP0iUet9DJnf/Dh6/taK7lvNAMuyzB6o5fK9G09ziWOvUwA4QCLVe3WnfjXZrluatTtEfZSNfcuy2Fkk5f25rPP37iWaKuhv+dLIMqUD27bVsWnP43sMKeau62SZknqWmcnPXqwnSTu3pml0Ii2D+8YJztkm9atZ19XPglQH/18b79DxAL8XCZeX6627Oj5dAZQq2rN9+q5c/Z3vgNTdZ69CltGiKLJ20xCCrMhVVaV2nciKv67rXUfMfw1J5LRtJaZ/RMqncWnnby2JBv/tNE17Ol6j5kHJWuD6B3NBALyEvu/rut62TTry/Nz4wBfckOHcb2maRmOWFnhTHT/Pc1VVEut1XetvK80UuQz5puY1Z2huaP5g3YKF89pYbC71Z3S81gz1d9av5kDHT9OkGmq5IPKAR8cDXAPN+z+v49XH+S3nxVbW+t73ffYq6ro2KZ/doSxLWeVTMZqKMPXIexf1D6KGza7n6B74cHNlQ8pO3lpywkkHQm+jMmzqmD3ESO9zADiDQjwjkaruWk4pkZ9MZHN5QsdrpVfqNpozmOeJPc6Rnu66bhxH71cjBxhz7JmmyTz3smuD3j8+qv+ejl+WxQ+yXsfrvN5pfq9NFEqkvlq+iP6S07//Buh4+BB6uqqqWpbFqwEtpWlNXzpV27WbnlXtoAdeispcfq2QyHVYp7Bj5Syhx94coOVTKBu21zeKyLFKmo7vXAStdRA6dST+zut4XaOcAn2bpDJ9WRbpSNUn2xNJrOuSI8WW6nh1tS93Q7ooao09c7WGDTXXwf1j3ineSd3fsdGta87r2VtFZ4k2PjpFjLKzZaejFp/tH7QUrZJnvwKAPdZ1res66mktTknmA0+083M6Xhula0MIFuHa971M6fKcyZZvOl6WeKlndQvK6qhpyTzPfd9nRyLT8UrUc0bH63SGLQWod9K3d3W8lhy17CA3QvV46HiA76IFL/3tXQX0tOtJU2cnGeFD+sycoOfZpGdqJo/s8d51RI+3uoAoqDQqymJGIx1vekh1NtOsxH0kkc+LLWUSiOqTxWJ9ZD3NKiqJdfmBRFo/1fGqJPGLQr/7gcVdel2D38H9o3s1GmNstLObXPewBps93VxVVVqf87fWsiwWresXrLMn0lEWHpDdTZfJxA/gIWRLTrdXVaWhUM4n5hce7fy0jg83+3QIQc73ivaR97wmEtu2zfMcjQ7S8VLqkY63CJyu69StZa/OBs1hGM771Xge9auRecVn1tcWdVnoeIDv4s3bIQS/nOefVS0FWp+S+pz43ioVNJGO9+uG4Sa41WtoT2/790VJqaf2+OhEZp/4jtHUF2jqMDXGS5rbf7W4kUpwazrNYfw+qY7XZInENeK8jg/37h+pYf/r++Bj/TSaYR6kMd77dR66tWxxxtR86uAevXrmwGtL18XED+AJ5OLiAzejOFdv7fJIszaHRCOpP2mUy0Vp3HSIUkBq/dkfJY2u+bzKV7iq7A6yi+tf+1ajoZWm3lLdyEm/Gh1uZoLIr8by1WR1vNx7FJ673tLPa1lDqwcHOl6mtIeyef420PHwCaQ7FYpuGyWXo55LMsIkcmrqFhaW5w+PdLwZIz0SQFkdFnnpHOh4n5hSbo5R9R7V8cE59omoT9H7OOy/exGZXqyrknaZ2SDFNBTyn+Wkjj+YB/pb0Yd/KWWyL0p3/rFtWwPVN3W8HWJqPo2B9s5sdmnZ8qP3KgDAecyqvafjpYnTif137PGyrMvn3qeeVHYaea1EBq9wS/Zi3u2qqtziZZIwulseTPUq0vQqtsj5x0cJuCIdb/OEyK+mu2WNzOr4aZrUkfqAovHri6gOdLz1xtc10qPj4RN4u6AtzOlRj5SKdpNozup40xlpAj6v42XO3LMdflPHey11oOP3+gVvnY06UHPojzrl1IdSRKItEuuquUIY0fHHHPvHm6OXGvyujve3UCSUhe7tg5HjWMc/cWtZhLQ/NnLoN7Ka4HgKAQAHpI4iaXRp9rl+TsdLZ1uWLXljymJtb4qY5zlKWGmlRVnqbQais5iTZ2Sbk7tOyMW5at3PHHWyLeCbKPv3sX+83+grEL6moUzbubu9rfaghX8z6Hj4HHpfnekhPWlptiyzU6Y6XtP99faWuAMdHw5F6jd1vHcwyPrVSPbt+Rn7/bOOy9JbduGpQddqFYmqvVdEabKBX80xavZsiEIUFHFXx4fbjaFxKypNFqY95yix9+ucv7X2fOv9dhuPPXoG03bArwbgacZbMkQvjr1cfqGOX9dV75yybt+bcvyJskE4Ur2RN44tGoRbT7Lup870MtrcZTWs6xB99VodrxPt6XgrDf94gGdIl7EUzCpfBa8YvJ9fpOMjZXNXx1vaFh/4cuDffF7Hq4u0PjFdNAhfPSs8kShXRt5on8jZcc8Px3fTIntGmztFX6krRJYZkVg35EAZmbrv6njdRZYwwZjn2VS4j3lNyQ6x4fStlUbQrrcXyth/93xqs+0wkuAI4FnG2yvGvTj2cllRoemBT/vVKNuM/W3djjnSqAdIjQLyxvFbJLi9Ah5ur4mVr3x6sV7He5O/Zi+qcDT639Xx9n6rbJtEh/gdfAq4VMcvy3LpV6mg4+ET6M0RPg2fz/1i0X4+IYYlXfESVjln5I1nL162yb1UkfUpFuvpUWmRKTRrbbXeTd9a+KkqaY99Nu9kuNk/vE+FbCRRaKNdRaQRrRvVIdlWVftYPaXss9191kMJWZYS/dbhFi9lGV3E8f1jpIJbd4WPeS1uyVjTymTzTobTt5ZufpuOyrfNzq7JyUFcXbra05F3EuBZ/DtWhbdGaxKe7b1fouPVXWjotPM2TaN41qgf2NPx6jF8dkhNRSTN/f6RjPajjJ1d0bTRUZF217q9wuHutol39I8qEF1dFOfqY5+uCDoePoHc2S2hdTQF94kXvXe7EQkmE75yFxnHMc0fr3J8hJ9lCbTTSan49N7l7SXSwpSZT3Kf5pOpdt6Po6VSX6u+71O/l3DLWB/VM3wN1fWNFrVPRNbPJw1w7HgPVI51Xf09kP64x/eP3zMykJszunaLfsTUIJR9D5RV8sytZanutY8JhWyeexE9Sv6K9u5zADiPvfTU+9Uo44oM9nsLpwdITEcnMhuQClenoVVc+bh6q7yfRUjp+vK9M4wRJZRUURZBm10z1LXsKeZUx1tHZ8rbErJFp07ftOV38O5M0Rq4pX6+bueGjgf4LuMFX1kvI8SlFxN/P9/PZfZ75lpKVXGtmxzgNyBJamherb/rupZolve5nrLI0eVpe7zM2Ou6+iBO6XK9zsn2lOuLz+iStcfbzqpz0zRp7zTkXq0YXcuejpfO1t9e05shT+vwWiD13dGavGkr1fHeohGtHsjO9fI3wX8MdDzAC2jbdi/08Hciv8yfrsVfZkiyMj+BbEU/HsMQZYsDgPPIpU3iWM4tB6JcbujR4dk3P0RH7S3cRS+Wko5PS/NbUtN79OzbQl/WTqE0OHs+Qtlwr+wV7Y1QtpRhW1KXpGma0sP1Q/jXsQtl/7xbpV8LOh7gNWQ7iF+I+jLS1LwJ75PzktgDjXw/uOa7LMtvmEsAwK/iBwe7p0/9+wfoJ0DHA7yMYRh+v4+dHB9/uhZ/FrnL20sSXkXbtj/lBOUDNgAA4FeBjgcAAAAAuB7oeAAAAACA64GOBwAAAAC4Huh4AAAAAIDrgY4HAAAAhFglGAAAGjtJREFUALge6HgAAAAAgOuBjgcAAAAAuB7oeAAAAACA64GOBwAAAAC4Huh4AAAAAIDrgY4HAAAAALge6HgAAAAAgOuBjgcAAAAAuB7oeAAAAAAIIYRt2/6p814ddDwAAAAAhBBCXddd12W3931/cOA0TV3XrevqN47jOAzDmfPO81zX9bIsB/uM44jcj0DHAwAAAEAIIVRV1bbt+e3GsixFUUzT5Ddu21aWZXZikNJ1XVmWB0q9qqqmac4U9e+Ajoe/Rtd1RVEURdE0zfHMfo95nouiMMND3/dVVZ20KMAB27b1fV+WZdTRAwDAL6Gqqqzs3tturOtaFEVkjw8hDMOQ3R5C2LZtdczz3Lat/p6mSdMGb4Ovqmocxycv7I+Cjoc/RdM06mjGcTxvA4jwOr5tW80K0PHfp65rNSY6HgD+PLJPe/w4Mk2T/8osUFnquo4KH8exaRrboWmacRzneVbvaiNXluMeWHp9mqb1K9quv5dlqes6kuZ7Ot4UuWjbdp5n/T3Ps0ZtT13XGr5Vjaqq7PLR8SnoePg7SH9bB/EqZEv4R3T8NE1vFdkaq06eou97XCEB4NJoBCnLMhW4Jo5ti4wdUb83jqPX8du2ScF3XWd7TtOkjV7mVlUVlaZjsz1w27ZN0zRNU5ZlVVVVVfV937atyeuyLOU6b2hYXNd1HEf5wWusVFFt2/Z9PyR0XRf52Ucr55Ejvtfu6PgUdDz8HdSJPOdLc7fYf0TH13X9Vh3f9/1JHS+vSnQ8AFwdqfOsY0lkaJcdPe33vD1bpWXlbNM0fqjKzgrmeT4ezp7wq5HxXusPy7LIZn9wiohxHM363nVd5IWPjj8GHQ9/B2lEdPzTnBfZHziFbEvoeAC4OnKhSZO9pLlc9nS8ofFoL95027a7Ov4uZ3R8tszUr8a7tq/rejyMruuqCkcrBuj4Y9Dx8CHUPVVVtSyL785sNVAugPb0ajd1Cn65UL2YsL4scjS0HtOOVdeg/sVHWw7DUJalvrUqDcPg1/VMx/sI2r+nLyN/Svsh9CuIqHO332IcRzWXGtOXYB6iZVmGRMdv2+bPq15+2zbzpBdq7WmabPtzkQ8AAD9CVVXqAz2pi3lWx3v5qz72pPtoquOPE0daVbuuU69uxnXvH78sS1VVqTnGdPy2bRqvlV5G7jRt25ZleVDzYRiqqprnWQN0XdfaGR1/DDoePoHc7PS3XzUbx9HUm83FNYP3ilw9yDAMUoF6tlMzeWSPX9fVUqNM0ySfv3Az9PpJvy/KZGuk4y2vreqcRh39AXSlvneu69pGGmsHfSVVrRFCUcXanvpoak/9Hen4uq6rqlIhOtB6+Wg8k4eor8lxBjQAgN9DOmAty5KmUEx1vFlJwi0GLBX6e0Q6fhzHu92mRltL0SYnnDHHno5v29YiWb0JfxxHDcHZk8oRX1VVEhvp/m3b0PHHoOPhE0RhK/a3+gvbrk7KvKLVB3k/ma7rbH8ZeqNi/f4KsvHHmr6M1GRUlJR6ao+PTvT3epNIx+u//jIltdUyfd/7yYxfb5UpxR9lhUQt7xMSR2ePxrPI/KP4rYdcMAEAfgp1jH68k8072i2bZyYajFId7y1fQuNgtLB5bP4YhkFBro+metu2TX7tWiuIOupjHS9HIIl4G2S7rtP6+TAMxzpeKwPpssY/BToePoH6Jq/nwk0upxEtph0PfPuU0z06PNLx3scj6hCzOj7y0jnQ8VGC+T9DpKTVwn4epZ9MfbGZ51OXR9+86mezXxnrutoyiJXmdbxZoSLIXwkAV0G2JPMeTN1sQs4er4Vo/W0epFnZqm+9DSUaQ5WdPVs3yWXlbo/84DVwRzRNY2untkatCvi63dXx4zhqiJGPq471Brtw6Fdjzq5/z6x2HnQ8fALLkyUV6L1Zom5Fu6mny+p4Cb6+79Vl7Ol42Sf2omq+qePTpYC/QaTjNRHyOt4WTPRfn/DYt483yfd9n66ZeP/4pmmU4CxqZz+e6Rd5eUZRAICPoYHD7CBZm/exf7wcV/ZkazSQhdwYehBp6hc/rW46Y+pao047KjaNc/WvUDzwq4m+TXW8FRLpeIXA/eM+luh4+BzLstii4bIs3rhreCfptA/Sqp+6ibTPSu3xe17s39Tx2uHvZbDJ2uN9pykd7306FTScSnlr4aqqfLfuW14WIPuNDnT8X10AAYB/Cg1w6hizqdXu5qvRDtmh7YyOP0Oq41Pzf9ZPPavjbbdjHa8gV/2d6nirD/7xKeh4+ATe8CD5rmDWrDudPcBRHyQTu3VSd3W8ekxLUxNcTq5v6niLv3lJ4/weIh2vVvIDho9Llueitiuk2P/K+nHLsowsJb7lo+nQgY4Pt8UBf4ppmrDQA8CFUKd3YGPa0/Hbtqn3k/mjyOXs+m06Xv+1EdnreD98COWPt7+9jh/H0cpMzztN08uTTV8LdDx8grquLVejf1uTmeR9HhKJM+ut/COqOCGltVJ/17atPeTqs/wSZOoir9J0rF/v84JVWtOszvq2aRpz4yv+qGe2yfRlWbxrkyXx1O+onRXnqjZZlqUsy2iBIusK7wv01n2lbtDZVY6cdlQTW73xHJh2AAB+JxrX9pZzs2+MUsov60t9nnUTtRL6kY5Px9CTNXyJjlcGZ/vW63hvX7MC7QIjHX9wXpsXEecK8F7kzq6uJ3pjqPIJSpmZVo6i7yPBra5K4ThlWSoBVlavmzosXJZJH8JvbtmiLEufLt3nWPTl/NXZvyVu90FO5gQfKXXJazVLKuJDCPM8R32xn1ZpsLHCVVrh8ntqblA4xx4NA/4GeF9TAAC8AwV0pjZyP/SkpLpW6WX8Pv5lrmnemzNWee2T9Y+PSP3Uw21BQH/Ljha9E8quInIr0rXYfyMdvzrSfDXpqv6/BjoeAN6CzyMGAAC/GQWwyVbibf/FCXt813V6GYimKAo/jQxeMrfJddZbi+Z5jhJHRjpeFTMzUOROqZRof8/N9TzoeAB4PTKT/Mt9KwDA5dBbnOy/SimW9uR6savfMs+zXteqF1dlO399698hta6rvf7JMO9Kjwz8abaDtm3/6gr5SdDxAPAyvIMTxngAgGvxHeOLvY31ddXJlA8R6HgAeBn2wiZEPAAAwLtBxwMAAAAAXA90PAAAAADA9UDHAwAAAABcD3Q8AAAAAMD1QMcDAAAAAFwPdDwAAAAAwPVAxwMAAAAAXA90PAAAAADA9UDHAwAAAABcD3Q8AAAAAMD1QMcDAAAAAFwPdDwAAAAAwPVAxwMAAAAAXA90PAAAAMAvZV3XdxS7bdubdr4i171AdDwAAADA5zBpvixL0zTLshzs3DRN0zTfF5q+hHVdy7Kc5zm75ziO0eShruthGOy/y7LUdb13uMcubRzHpmnuzkn6vu+6Lt1tnuczp0urmpbf9326fZ7nuq6Pf4hxHH+h3EfHAwAAALyFMUdVVW3bhhCGYajr+kDdSnD3fb8e0ratl7npGYdh8MK9aZq2bdd1naYpPemyLFVV2c7rulZV5SXsOI5lWUaidpqmvu+HYei6bhgG/V3XtXRz27ZN09xtrq7rqqpK27Asy6gOnm3bxnHU31VVHej4ruu6rtv7Kr0oT1VVZy7hw6Dj4dPo8f7pWtxB3dBP1wIAAK7NNE3rukoZD8NQVZWUt/Ri0zRd15naTjW9dG13Aj+wTtM0TdPeSf3O0zRlzeSS3eu61nXdNE1d113XSf2rBP0RsW3buq5FUeikfntZlmoKIYt+Os56HT+O4zRNOq/s6HZsVOdlWXTSEEJVVabpfQWsfNPxqq0xz7PmNpre6AK9DT5b8o+DjoePYuuDxVf8w9y2rf9Kj5CeW21pmmaapnEc95bAZHiIZtV931uZ6fJcXdf2bVmW67pahwUAAPAdZNKWJd42LstSlqWJeNmDvVKUMX5ZlmNL/J7VKT3puq4S8TpW522aRkLfH7ssyzzPEuVWATN1e2t9etJUx+ss2aWJ6HDT8apqVVUa6MdxVLFaWyiKwh9ryxpWSWlxmxfZnMHr+HmeNY/y1HVdlqX+nqapqqq6rrU/Oh7+dfTA2H+naSqKYk8rV1Vl633zPEu+24GS3Xs6vqqqaG5gaJIgpZ5+qx5zr8IAAAAPMU3TMAzStX3fS2Vq4Ov7vm1bk4apfdo0uvTrAdmTenu8DMxSwPLq6ftex3qBLpO5FeLVs+YDsqCZtA0h2NmXZdFSdlEUkuC6Uhn1I90fDd9yizcZ3batxLRNBmRxV900VfCDuJrOKmmXZvY+k+CpX01UE3MEEl67o+PhnyayQ4TbY7nnY+MjTmSJ9/Z1LdJldbwm0EVR+I7GU5alOrLUDS6y4ssWknUfBAAAuIvGPi+ptWK8LEvbttu26V/t5gcgqf9lWY4VfDbe1KS5TR70r7xHZNIOIczzPAyDzm4S2Wztfd/LiBbpeBm/tbpeVZUKt2PNxcVXYBzHsiwbR1mWftJiLi7S7vrbG/W9do90/DzPXppn1faBjtdKiKzvqb8QOh7g/7FH3Tiv47PW977vszq+rmuT8tkdNNfPCv3UG0fmgXsXBwAAkMHreJPC5vuhHdq2revaa8Rt2yRzpbzNhca7mMtTPLv4LEnt/WrMlKaN5l8uhe0HYnNMlSndK2ZV29YNom/tpKbj7dQyiq0urNYcZiIi//gzOr7vez9we7WtGUg41PFWvpSGHHezpaHj4d9FLjTpstpJHS/X9shxUEE80VG23mdLe2nJ6qFk449iz1Mdr1XFk+muAAAAPKZlpdRTL/kQgnfCjliWxUal6EBJ+cjDxL6SL02q49u2le3Zdp7n2VvH13WVMlb+R4nypmkkzeUIpLE1rc/e5EE10dk1PdjzbjUdr+w3d3W8JckxFBasv6XarUphX8frwHme+74vy9JWOdDxACGE0HVd5BgTHtHx27ZZHGo0V44wb0I53pRlme4jsb5tm2z2/pFOdfyetQMAAOAuZn1XXppUx7c3sh4yEtBCTuT2t2xbBzpeln5/UtVB46M5kEiyR+pWHva2LKBTW/CrJc30tjA7qUJa/ZVqGhNc5K6qndZcwb4WFHvGHh/xqF+NLqfrOo3+8vCRg750AjoeIChyJdp4XscLn3Am++IMPXL2XznPpBLcxLo6FL9PquOVWofENQAA8AQSoxqzNOjIpzzcFpBtANIYV7n05z732jRNPl5LaWd89KdHklqO6TrQJ6VRsZb7JRsGZoGnwlJPyiQv+a5g2eikymQvG79OKvu9SXPNQzSw2iqEWd99nvjzOn7cyQ5pzktZHa9ZikS8tbmqKu/8Yx1vCxQn7oI3go6HT6CHM9r4qI4PIchjby99ZPSeNjnzHDvBK4inKAr1Ytl3QGiJ7dR1AgAAOOSAbjJR2lEiW9Zxv3Pk8SLJq7+j/GmmXKtcCkhJatvf+6hY/gaLJY1CToUFm2qk1iTEe+rP8+zTygUXXBudVPGjktRWpvxqJLK1PmCK/1H/eNVWq/GRX401QlbHWzYbNYIK7L6+iOpAx2tJ/2Bl4DOg4+ETHOj4vcSO3nku0vrrusq7PXUxLHJE84FIrMswoJU+dDwAALwQiVEfnCp9Kf8NCV/vKpN9Lau3oPstEtOps4dKTqsRbi94srNEaRZVK3NnD857XhGuGrLlUZNmeMteabgpYOVr13wgqt40TfaOqkjHyztIRrcDHZ9V2/b3sX+8nzCkOt5mJlFTz/OcfZXVh0HHwyfI+tXIZWXvLcd+f4XFRDtItVsnYhl5PdLo0TRg7xVRmmzgVwMAAK9C9vjIR8WnjrE9U/Ht3wVrFnT5ychArpwN2Xw12ZNKjuuocNOvftST1PZDs3eCNyGbXU7fO2lwiwZyYkkjfQ0vo4dbtnuL6FXUb+pN9E0d7xNcpjre9sc/Hv5dsnGu4abv0+2RKNeTH+1jLoZWVNYPR9Gu/hTZM5q7TvSVRevfv0gAAICvpJo1SgFp21MdL2RBt8Q1ZhQXXmeblX3PNG47KO527wUpfsz18wRzpJGRPtXx2Sv15nNFylouztQjKNLx5tOvQqZp0twgGsfv6njbktXxfmOk48dbZv2Q0/H+258CHQ+fIJt3MtzeSq2M79oix7vq6zuiJbK9VV4WdHuidEj21DLbWzcnZZ998JQSh7yTAADwKr6v45dlkW2rrmtJWG+0Ml/z4HxQD/xqbAfFoWbrbL746y1BpFnE9YdS5USO9XsntT0NafG6ruu6Tt/Z4guxK/WTgSjXfshpd0t3k0YgZM2CPoD4QE740qRDftztFh0PH6JK3gMl1nWVtd6I3ukQbn2TnPPS7JPKOePDVYVcYvbI+vlUyUteO94DBQAAz2J5Jw1TiustUaO5vO8pyHAzcjVNYwnOTVM2TdO27bIsplAPXFzCLZu7hYFm3VZVlAJGl2WRN7zWve3UZpW3FHAHV+rLT9fYl2WRp5Cqmm3Gg4jSrI7XnMdCafVtquOj7JmRjvdrGmm+mnTB//Og4+FDaEb+s7f7o8h4f5CuHgAA4IC79vi7On6e5+iFr8r4bqYrleP9beRSH/nVKD990zSWuHldV3m3Rk72KmqaJu/gaqGufjXAp7u5uwhguSzTgXVdV81P9hxZj3W8XzM3tT3Ps1V1HEdzyPEmRcWq+mLTBQHlks9mycsG5n0YdDx8Dks6exWiPF8AAAAPsSxL5NohP5kQwrqu/qtt26L/9n2vHO1Z305ZyvW3FLmNsMr56HeWOT9blMSoV+eKJfV6WjOHbJSnmefspVH+SqO4NXkB7WnfA1ksIX7GFJgNlrPyvdeuzP9RmT7Xp6H1jbRJs6sZHwYdDx9FloDfb5VXOP+Pz7MBAABO8vvH1vDTlXz67L+2bdHx8GmUJfena3EH/3Y3AAAAgF8IOh4AAAAA4Hqg4wEAAAAArgc6HgAAAADgeqDjAQAAAACuBzoeAAAAAOB6oOMBAAAAAK4HOh4AAAAA4Hqg4wEAAAAArgc6HgAAAADgeqDjAQAAAACuBzoeAAAAAOB6oOMBAAAAAK4HOh4AAAAA4Hqg4wEAAADgx9i27aercFXQ8QAAAAAQ+r7vum5d12j7PM/zPJ8soW3bPV0+jmPTNOm38zzXdb0sy0HJ4zgi91PQ8QAAAAAQuq6rqiraOI5jWZZVVR3IaBPZXde1bXuwW1q+nbosy4NTVFXVNM2dC/j3QMcDAAAAwBcdP47jNE1d1zVN0/d93/fruq7ruixL0zSRzb6qKsn3ruu6rouKNXXudfy2batjnue2bfX3NE0qzdvgq6oax/Ftl35V0PEAAAAAr6eu6yKhaZppmrRD27bpDkVRlGXZ973tFrEsS9d1tnNd18MwhBD0716ZYq9MYTp+XVf9LV+XcRyLohiGYRzHYRiKovCSep7nsiznedZR8sxZlqWua3njmJHe6/h5npum6b5S13VZlvp7mqaqquq61v7o+CzoeAAAAIC3sG1bWZYmRqdpkriX5hZVVZVl6Q/p+16yO7VtS8E3TWPe5FLP0c5VVRVF4d1Utm3zUwiP3OJNRrdtKzFtmntZlqIoZINf19X+9oeP4yj396Zpxhs6nRnpU7+ayCe+ruu+7/1VmHZHx2dBxwMAAAC8C6/jw00Te19wqefoqHVdpcW9Ok/1ujEMg3dM12whcjef59nPHwxzcZF219/DMJjm9to90vGaHvgaZuceezp+HEezvqe+9ej4u6DjAQAAAN5FpOPDTWSbaTyr40MI0zTJKi+j9TzPRVHsxYmGELyAzur4u0T+8Wd0/DiO3qbudfw8zzKuH+h4K18VjlYM0PF3QccDAAAAvIundXy4ucfIiN40TeSQc0Cq472/yh6m46dp6vv+ro6XCX9wyK9Gf8vfRob2Yx0v2790v5pLjvXo+Lug4wEAAADeRaTj5THvTdoHOl6ONPI20VHHgapGpOPHcTxIB+lPV5alObifscenJTzkV7Oua9u2XdepqvLwkYP+tm3o+Lug4wEAAADehZKvmwiWwvbW8QMdr4BXvSNpL+FMlBVHBvs0Vc6Bjjfru88Tf17HT9Nk/438aixfTarjt22TT78s+na4kloOw4COPwM6HgAAAOBdyI5uVFUV+cacscdv26bDs1pWNv4odtbb45WdPXsKHSuV/IR/vCqp3JeRX03TNFqIyOp4c6wfhqEsSxUYvYgKHX8XdDwAAADAu0j94yNO+sen6Wuis/hCUv/4A8f6aZrsbayRjpdDjkJsD3S81Sr797F/vN+Y6nirNjo+CzoeAAAA4F08reOVr8as7HoBk5mu07Mc6/gzeBmt01kaSqXN2bbN55K3o76j432Cy1THW2no+CzoeAAAAIB38ZyOt/zx3o6ulDXZ0t6h471bv1zzm6aRG70v+a6ONwf6rI6PDvE7jONoEwZ0fBZ0PAAAAMBbMO/zg30O3ueaOsNIykdO9nIx94VoDhC9LfUukYz2r4w1G3xd15GeTrX7NE16t2vkBZTV8VVVWfBuVIFoN3R8CjoeAAAA4PVESWPSSNO2bYscVVX1fb+X21EZ2f3+dV33fS8beVrmXav8sizLsigZvH85qzGO48lck/p7WRbNNyLlnep4hcP6ovwOqwMdnwUdDwAAAPDvsq6rXsCUXQEI93S8/Ob1t2n6dV1Ndi/L0ratlh28U9A8z3VdR6720YKAcslrQqIsluBBxwMAAAD86yibe/YrOcmc8bbv+34vMc40TWVZmhaX+T8qUwkrowPXdS3L8sz7aP9B0PEAAAAA8HYejbv9/oF/HnQ8AAAAAMD1QMcDAAAAAFwPdDwAAAAAwPVAxwMAAAAAXA90PAAAAADA9UDHAwAAAABcD3Q8AAAAAMD1+ISOL/5X8OHDhw8fPnz48OHD5+7nAY39Pvn+3zl+ujn48OHDhw8fPnz48LnE5wGN/T75/t85fro5+PDhw4cPHz58+PC5xOcBjf0++f7fOX66Ofjw4cOHDx8+fPjwucTnAY39PvkOAAAAAABv4v8AlKq7Bi9xFhgAAAAASUVORK5CYII=
目前已经上市的5 个药物分别是Nexavar(多吉美)、NOVATRONE(米托蒽醌)、MIRIPLA(米铂)、MILICAN 和ARGLABIN(阿格拉宾)。索拉非尼(sorafenib,Nexavar)是全球首个被批准用于晚期肝癌治疗的分子靶向药物,已被证实可延长晚期肝癌患者的总生存期。它是一种口服多靶点、多激酶抑制剂,可通过抑制血管内皮生长因子受体(VEGFR)和血小板衍生生长因子受体(PDGFR)阻断肿瘤血管生成,又可通过阻断Raf/MEK/ERK 信号传导通路抑制肿瘤细胞增殖,从而发挥双重抑制、多靶点阻断的抗肿瘤作用。该药已经在保加利亚、埃及、伊朗、拉脱维亚、黎巴嫩和乌拉圭批准用于治疗肝癌,在韩国、日本、中国、欧盟、美国等也作为肝癌治疗药物上市。Mitoxantrone(NOVANTRONE)是蒽环类抗生素抗肿瘤药。作为肝癌治疗药物已经在加拿大上市。Miriplatin(MIRIPLA)是大日本住友制药株式会社开发的脂溶性铂复合物抗癌药,于2009 年获得日本厚生劳动省批准,用于治疗肝细胞癌。MILICAN 是一种治疗肝癌的新型放射性药物,由韩国Dong Wha 公司开发,已在韩国上市。Arglabin 是一种从生长于哈萨克斯坦的苦艾(蒿)类植物中提取得到的倍半萜γ-内酯,由Paracure 公司(NuOncology,Labs)开发成为一种抗癌药。它能够抑制法尼基转移酶,Arglabin 是目前上市的唯一法尼基转移酶抑制剂。作为肝癌治疗已经在哈萨克斯坦上市。
(2)处于临床研究阶段的肝癌药物
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fY7gPVatVB6wOAg4DK1IDKOCJUQ2VMgMq0yPT0NDOYhdMX/mto/U4kZgBYIKAyNaAyjgjVUBkToDKtQMmYrQOPd0Zi0ktXUkoGKgPAAgGVqQGVcUSohsqYAJVpCuVjOpOM4SVGeWFs1b0boTIALARQmRpQGUeEaqiMCVCZplSr1bE9BztmMPSfu/m6n//LP1wClQFggYDK1IDKOCJUQ2VMgMo0hRnG0Pqd6aUr58tdhtbvHNt9gDeYarW6f/TQXT9ed9Hp15/7xeugMgAsHFCZGlAZR4RqqIwJUJmmVKvVVfdu5IVjbPeBofU7yWxa+aJfNooLcWBsMnPbg/feMpSIit/9xh1XRG6DygCw0EBlakBlHBGqoTImQGWaUq1Wv/Dfz/76P1y6KbttbE8dF5kVr778xqsvH3nyQWXNndtXL3/sg/X5dqbvvF9AZQDoGFCZGlAZR4RqqIwJUJmmMJWJ/nPiO19JXnpG6sozb//Zjfc/+sD/lgaf2755ZMeW5x8f2vXE1hefzO956sE98oOK/ODe4Yf2Dj/80tOPjG28Z5i+PlifK2l9NnxofaAyAHQWB6jMyMiIIAgrVqww/qj64fnYdX+ndaAyjgjVUBkToDJNqasy13zjjmu/dc8Pzvu3pd/+5Y8v/NUNF61KXZK9+dJ1t1y+4bbL7789vil95QP11wcqA4ANsLvK9PX1NdKUY8eOdXd39/f309VzYmJi0aJF7Ns2gMo4IlRDZUyAyjQFKgOA+7CvypCpCIKwZ8+e7u5uo8oMDg4uXrz46NGj/COCIIyPj7f3X4TKOCJUQ2VMgMo0BSoDgPuwr8pMTEycdtppU1NT5DQ6ldGlZNhfWbRoUdvbTFAZR4RqqIwJUJmmQGUAcB/2VRlGXZWpay11/aZ1oDKOCNVQGROgMk2BygDgPpytMsPDw8bfbF1lltVjPp/67IHKmAOVMQcq0xSoDADuAyoDlYHKQGWgMlAZAByMs1UGG0xQGagMD1SmKVAZANyHC1UGZb9QGagMVKYRUBkA3IdTVcbkBJNu16l1oDKOCNVQGROgMk2BygDgPpyqMpqm9fX1GfvK6B6ZFVAZR4RqqIwJUJmmQGUAcB8OVhlde985NpXRbK8y537pWkEQvvJ35/Mqc8NFq085+aNCPc76/BVQGagMVEYHVAYA92FflSE1MUZofv+IdQQm2u7zS9hZZT7zf/8jvUadytTNypz/5T5BEH5wwc+hMlAZqIwOqAwA7sO+KtN57KkyF33t+pNPOkUQhAvC3/d95M+bqsyy+AOf/uvPfvLjn1p25SaoDFQGKqMDKgOA+4DK1LCnypz7xWs/+fFPffecO645545WVObqbywXBOGKM29BrQxUBipjBCoDgPuAytSwp8qwWplWVGbZlQ98+q8/e+rHPnHjJVmoDFQGKmMEKgOA+4DK1HCByiz9Tubkk045+/NxnGCCykBl6gKVAcB9QGVquEBlPvc3XxcE4YcX3AuVgcpAZeoClQHAfUBlajhdZW65fMMpJ//FF/727OVXbYHKQGWgMnWBygDgPqAyNZyuMnQG+4cX3IsWeVAZqEwjoDIAuA+oTA1Hq8zNl60/5eSPfvLjn0pfOQiVgcpAZRoBlQHAfUBlajhaZa46+3Y6g43BBVAZqIwJUBkA3AdUpoZzVebWyzd8+q9PO/Vjn7jx0ixUBioDlTEBKgOA+4DK1LCnypz7xWtP+rOTjQMcYl9LMpW58qzbBEE46/NxjJOEykBlzIHKAOA+oDI17KkymIzNA5UxByrTFKgMAO7D2SqjGye5ZMmSqamptv81qIwjQjVUxgSoTFOgMgC4DwerDI3OXrFiBX1LWjMXm4HKOCJUQ2VMgMo0BSoDgPtwsMoMDg4uXrz46NGj7JGRkRFBEMbHx9v7B6EyjgjVUBkToDJNgcoA4D4crDJ9fX06lRkcHITKQGWgMlAZE6AyALgPB6sM5WD6+/vp6kkbTOzbNoDKOCJUQ2VMgMo0BSoDgPtwsMpoM2kYQRBWrlzZRtnvsnos3LNtBaiMOVAZc6AyTYHKAOA+nK0y2kxuhhgeHp7V34XKQGWgMlAZqAwATsfBKsNOYo+Pj1er1Wg0yu83tQE2mBwRqqEyJkBlmgKVAcB9OFVlyF3qlv2y49mzBSrjiFANlTEBKtMUqAwA7sOpKqNrKkPMsfIXKuOIUA2VMQEq0xSoDADuw6kqU9da6EFkZaAyUBmoTCOgMgC4D6eqjKZpfX19ulJfY6eZWQGVcUSohsqYAJVpClQGAPfhYJXRuMPYmMEElTn3iwlBEMLB840q89lPn86/T354wb1QGagMVAYA1+BslZlfoDKOCNV1VeYz//UfSVOMKnPuF7935j9eRlmZZVc+8Om//qwgCD+84BdQGagMVAYAdwCVqQGVcUSo1qlM7Kv9J590iiAIF3z5+76P/HndrAy/wbT025mTTzrl7M/HoTJQGajMHDkxw/T09PEZqs2gX5uenp6enj5x4oTVLwK4AahMDaiMI0K1TmWi/5z45Mc/9d1v3HHNN5a3ojK3Xr7xlJP/AioDlYHKtAGJC68s+/YcpK+tAzu3DuxcnlzFvi4+/Xr+iz1Ov7l1YCeTG9Iaq18ccDBQmRpQGUeE6ka1Mi2qzNXfWC4IwhVn3gKVgcpAZVqB6QtzF6YsOllp74s5jRMXB9gEqEwNqIwjQvVcVGbpdzInn3TKJz/+qfSVD0BloDJQGXOYwezbc3Ae3aXu19juA9Vq1f7vH2BPoDI1oDKOCNVtqAwdbiI++fFPpa8c9OAJJv6El05l6p3wgsp4WmWmp6dnEjCPL5y+8F9D63ciMQPaBipTAyrjiFA9xw2mzwW+LgiC12pl/ua/fo4/4cWrTPSL3/v8Z85cduUDy6/avCzOTnjdC5XxrMpQJqZjEpNeupJSMlAZ0DZQmRpQGUeE6jmqzB1Xf2AzP7jg515QmQu/8mM64XU+d8LLZIOJTnh94W/PTl+1GSrjQZWhfExnPIaXGGXXvt3P77X/+gB7ApWpAZVxRKieu8qc/+U+76jMt/7pez0f/9TV31j+XW59TFSGTnhBZTyrMiQWC1oWQwbDJGZsz8Fb+35x5ucuz2Y22X99gD2BytSAyjgiVM9LVubUj33ihkvWeEFlWK0MVIaAypjDDkgPrd+ZXrpyvtxFpy/E/tGJn/Svu/iMG87/Uh9UBswFqEwNqIwjQvWsVOaGi1adcvJHL/v6jbrD2F6rlWldZbjD6qiV8ajKrLx3Ay8cY7sPDK3fSWbTyhf9slFciANjk9s3P3/vrUOJ6E+/e86d8TNvg8qAuQOVqQGVcUSoNrbIO+nPThYMxL6WpFD9/fN+RsUiHp/B1IrKUEqGDnlBZTyrMv/4N5EzPnvxpjWPbF633egis+LVl9949eUjTz2orLlz++o7Hrv+otU/iq1c+u37+s7/BVQGzCNQmRpQGUeEakzGNmGOKkMF0TiMDZU547MXf/Ofrvl2+IeXnH5jPHLbT2+4/9EH/rc0+Nz2zYUdW55/fGjXE1tffDK/+6kH98gPKvKDe4cf2jv88EtPPzK2URzeeM/wxnuGl1+9JX3lZlqfWy7bcNNl62+8ZC1UBiwQjleZarUajUbZDffixYuPHj3a3j8FlXFEqIbKmDAXlfmHwBm0tYQWeVAZncp89xt3JL519/fP+7elF9z7wfpcnL3p0nW3XD5w2+X3335Fo/WBytThRDOsfoKOxNkqMzExsWjRov7+/nm5gEJlHBGqoTImtK0y5335WiohQrdfqAxUZl7QDdo07r6x8VX0ZfwFNnTT6pfiABysMseOHevu7p4vj9GgMlAZr6rMlWfdJgjCWaErMLgAKgOVaZtGszb5KZstnvliQzeZ4jh6ZTqAg1VmZGREEITx8fH5+gehMo4I1VAZE9pQmfiZtwiC8Pn/flb6ykGoDFQGKjNb6s7anN9OPGzipv0/X1bhYJXp6+tbsmTJ1NTUfP2DUBlHhGqojAl1W+SZnPC66dK1S/7L3xl/KgjC5WfeApWBykBlGsHP2qRxmwvaGXn50pW05WT167YpTlUZqvZdsmTJs88+y19/Z5WkWVaPhXvOrQCVMQcqYw4mYzelrsqc84WrBUH48v+MGlXm5kvXL/kvf8+uMKycCCrjZZXhB4YvqMGwLxq3CZVphLNVRhCEFStWsAf7+vpmZTNQGagMVAYqQxM066rM9RetOuXkj4Y+c+ay+KblV21mA6qWX7UFKuNZlSGP6ZjEsElVLxT2QGUa4WyV0W0w0YEmXm5mBTaYHBGqoTImQGWawqvMeV+67uSTfIIgRP/5e76PnGJUmW/98zWnfuwv+2MrWaimAV61yeFQGY+pjHXjNl++9rIUVKYRrlKZOZ5pgso4IlRDZUyAyjSFV5mzQvFPnPpXV0RujUduNapM/4W/OuXkj4b+JnLbFTkWqikxc/bn41AZb6oMpWSG1u9cUH3hZz7s2zN+a98vzw7FoTImOFVlNE3r6+vTNcSDykBloDJQGXPq1srUVZnEt35y8km+yOcu5ct+9eM2oTKeVBli7hM32dQq48iq4l5VvDEXP+v2S85IXRD+AVTGHAerjPEwNj0yPDzc3j8IlXFEqIbKmACVacpsVeaSM26AykBlGMePH981oii79vHaQSJCczTNv+g36w7arFarB8de3zn0wn23PfT98++9Nvqza865CyrTIg5WGcrBsD0m3bdtAJVxRKiGypgAlWkKVMYcqIw5x48fv+aSH59+2kWpxE83r5W2DjxeV0qacmj/m4f2v3no5Tfkh0bX/mRn9s7tN16y9vqL1vw4tnLpt38FlZktDlYZzTCAqe2CXwIq44hQDZUxASrTFGwwmQOVMYepzDlf+O4F4R9cfPoN8cit3z17+fe+efe9t2y579b8itsfWpV+ZPXyx7J3bl975451dz2+/idPbLj7yY33yBvF4Y3iMLsEpa+auURfztYHKtMmzlaZ+QUq44hQDZUxASrTlHlRGZT9QmWMKtN33s+WXnDvj75z3/WxVTdenL3pknW3XDZw2weXaFqfLdwSQWXmE6hMDaiMI0I1VMYEqExTWlcZkxNMV5x5C1QGKgOVsQ9QmRpQGUeEaqiMCVCZprSuMjdfuu60JV819pU59WOfuPGSLFQGKgOVsQ9QmRpQGUeEaqiMCVCZpsxKZa49Vzz5JJ+u2y/NLoDKQGWgMvYBKlMDKuOIUA2VMQEq05Tqh1vknfRnHzGO0vzOV37AZjDdeNGaU07+KPvRDy+490PrA5WBykBlbABUpgZUxhGhGipjAlSmKXWzMpiMzYDKmAOVsSdQmRpQGUeEaqiMCVCZpkBlzIHKmAOVsSdQmRpQGUeEaqiMCVCZpkBlzIHKmAOVsSdQmRpQGUeEaqiMCVCZpkBlzIHKmAOVsSdQmRpQGUeEaqiMCVCZpkBlzIHKmAOVsSdQmRpQGUeEaqiMCVCZpkBlzIHKmAOVsSdQmRpQGUeEaqiMCVCZpkBlzIHKmAOVsScuUZm+vj5BEBYvXnz06NG2/xGojCNCNVTGBKhMU6Ay5kBlzIHK2BM3qMzExMSiRYugMlAZqAxUpilQGXOgMuZAZeyJ41WmWq1Go9H+/v5EIgGVgcpAZaAy5kBlzIHKmAOVsSeOV5mRkREymL6+PqgMVAYqA5UxBypjDlTGHKiMPXG2yhw7dqy7u3vFihWapkFloDJQGahMU6Ay5kBlzIHK2BNnq8zg4OCSJUumpqa0tlRmWT0W7Mm2BFTGHKiMOVCZpkBlzGmqMku/fe//95//J5uveerH/rL/wpVQGaiMtThYZajad3h4mL6FykBloDJQmaZAZcwxV5l45JaPnOT77Ke/duNFa5CVgcrYBwerTF9fX39/P7t0YoMJKgOVgco0BSpjjonKfO+bd/k+8uenLfnq9bGV2GCCytgKp6rMyMiIIAjj4+PsEagMVAYqA5VpClTGHBOVOf/LfYIgXHnWraiVgcrYDaeqzODgoDR1AdwAACAASURBVNAAVj0zW6AyjgjVUBkToDJNgcqYY6Iyf/v/fOE/dP/H5HcyUBmojN1wqsoYQVYGKgOVgco0BSpjTiOVueacO/2f+sx/6P6P3/7KD/hbx2ujIlQGKmM5UJkaUBlHhGqojAlQmaZAZcwxVxlBEL76dxewrMxpS74qCMJ10Z9CZaAy1gKVqQGVcUSohsqYAJVpClTGnKZZGX6D6dpz7zn5JF/kc5dBZb73zbvP+/J1xoKHS864HirTAdyjMnMHKuOIUA2VMQEq0xSojDmzUpnrL1p5yskfDX3mzGXxTVAZUpnzv3wdsjKdBypTAyrjiFANlTEBKtMUqIw55mW/XX/xfySid0NloDJ2AypTAyrjiFANlTEBKtMUqIw5szqMfXnkJkEQLv36jdhggspYC1SmBlTGEaEaKmMCVKYpUBlzmrbI+8vu/7P/whWpi7M/vvBXp5z80Z5T/9Otl22EykBlrAUqUwMq44hQDZUxASrTFKiMOeaDC75/3s/+3//8P1hN67987mL0lTEp+7349H6oTGeAytSAyjgiVENlTIDKNAUqYw4mY5vT+mHsc75wtSAIkc9dCpXpAFCZGlAZR4RqqIwJUJmmQGXMgcqYM6u+Mqct+eqpH/vL/gtXQGUWGqhMDaiMI0I1VMYEqExToDLmQGXMmZXKfOufrhEE4bqoCJVZaKAyNaAyjgjVUBkToDJNgcqYA5UxBypjT6AyNaAyjgjVUBkToDJNgcqYA5Uxp3WVueGi1f/t/wr2nPqfbr1sA1RmoYHK1IDKOCJUQ2VMgMo0BSpjDlTGnEYqc9VZyz5x6l/96zl3MJX5+//2FUEQro3eg7LfDgCVqQGVcUSohsqYAJVpClTGHKiMOSZZmTM+exF/EvsTp/7VTZesxWHszuBslenr6+PfOuPj43P516AyjgjVUBkToDJNgcqYA5UxB5Ox7YmDVWZwcLC/v58undVqNRqNztFmoDKOCNVQGROgMk2BypgDlTEHKmNPHKwyOiYmJhYtWsTkpg2gMo4I1VAZE6AyTYHKmAOVMQcqY0/cozLHjh3r7u6GykBloDJQGROgMuZAZcyBytgTqEwNqIwjQjVUxgSoTFOgMuZAZcyBytgT96jMyMiIIAjDw8Ot/5Vl9Vi4Z9gKUBlzoDLmQGWaApUxBypjDlTGnrhEZSgls2TJkqmpqdb/FlQGKgOVgcpAZXigMuZAZeyJS1SGTmXb/DD24cOHN2zYUNefGLIsW6sy5k/PcgYGBqxVGasXoAkDAwPWqszAwIDVa9AEa1VmeHjY6gVogrUqY//1efXVVy1UmVdffdXqBVi2YcOGhYuSbeMGlSGPmdXWUl0WVGUOHz7M3gcmWK4y5k/Pcp5++mlrVcbqBWjC008/ba3KPP3001avQROsVZmJiQmrF6AJ1qqM/dfHcpWx6oUzlXnmmWcWKErOBcerzODgoCAIK1asmPs/tWHBVObZZ59t8U2ADSZzsMFkDjaYmoINJnOwwWSONzeYWAg7fPiwJU+gKc5WGSr1nReP0RZMZchnN2zY0MqbwHKVOcEx70sxdyxXmRMfxur10GO5ykxPT9t5fTQbqIydF0ezgcrY/P1jucp0eH1YXUSLIcwqHKwy5DFzOX2tY95Vhm0qtZ6Rs4/KzOM6zCO2UhmrF6MO9lEZq1eiITZRGauXoSH2URmrV6I+9lGZDrzYNkKYVThVZdikAiNtF83Mr8q0vqnEY7nKPPnkk88880yhUBgdHT148OCRI0eOHj167NixSqUyNTX1/vvvW3uJsVxlnnjiCVqi559/XrdEf/rTnyxfIstVZnR0VJbl55577vnnnx8bG5uYmDhy5Mhvf/vbP/7xj3/605/sEMitVZnR0dGnn376ueeee/HFF4vF4sTExFtvvfX73//+j3/8Y7VapfWxcHE0q1VGUZQnn3zy6aefLhQKtESHDx+mJapUKnZYImtV5vXXX9ddog8fPnz06FFan/m9/rQXwqzCqSqzEMyjyrSdkbNcZYaGhh577LFnnnlGUZQDBw68+eabv/vd7957771qtTo1NWX5ddZyldm0aVM+n2dLdOjQoTfffNM+ochylZFl+aGHHtqxY8dzzz1H6/Ob3/zmD3/4g01UWLNaZV5++eVHHnnkqaeeGhkZeemll1577TVaHzt4MFsfC1Vm7969Q0NDtEQvvvji/v37X3vttXfeecc+S2Styhw5coRdol988cUFukQ7ZVOJBypTY15Uhj+p1PrfolvV999/33KVefjhhx9//PFnnnlm9+7d+/fvf/XVV19//fW33nrrnXfe+d3vfveHP/yBbq87f02h9ZmamrJWZYaGhmiJnnvuud27dxeLRVVV33jjjbfffvv3v//9u+++a+36VKtVa1Xmqaee2rZtGyVmRkdHDxw4QImZ3/zmN7/97W9pfSxZIvb+sVZlxsbGtm/fLssyZfUOHDjw2muvvfHGG7/5zW90ny8L30LWqkw+n9++fTslPvft2zc+Pn748OFSqfTOO+8YP1+dfP/Q+lirMm+++WbdS3SpVDK+hdp7/zhoU4kHKlNj7irTXkaOPh7vvfdeuVx+9913rVWZtWvXrl27dt26devXrx8YGMjlckNDQxScjPeRHbvU8ktkrcrw67NhwwZaH/4m6fXXX3/nnXfee+89Wp8OLA6tT7VaPXbsWLlctlZlHnvsMbZEAwMDGzZs2LRpE1siSomXSiW6jzx+/Hhnlmh6evpPf/rTsWPH3n77bWtV5sUXX+Q/X/fff//g4GA+n9+xYwfL85VKpXfffbdSqXRsfU6cOEFL9O6771qrMsb12bx58yOPPPLEE08899xzL730Ep/n61gSlK4///7v//7uu+8eO3bMQpWZnJw0XqI3b95Ml2ja1eUv0bNdImdtKvFAZWrMUWXay8ixIPTOO+/QrqflKlM3CFGc7nwQ0jRtenqalujtt99+4403rFWZdevW0frYLQix9bFcZXRxiJaIkjQUhzq5RHwQKpVKExMTlquMMQixOD2XIDTHJaL7hFKpZK3K7N6923ifoNtssuQ+4b333qNLdLlctlxl2BLpLtEHDx6cy62U4zaVeKAyNdpWGX5nscW/Qrluug16++23Dx06NDo6+swzzxw8eNBalclms9lsdu3atexqu3Xr1kcffbTDt9S6y+v4+Ditz8jIiLUqQ+tDl5KNGzc+8MADW7dupXx4J0O17vJaLBZ3795NmTNrVebRRx9l68NuqWk/jr+l7kCo1t0kjI2N0RJZrjL8W+j+++/fsmULlYYYb6kXNOvJG/DExMS+fft+/etfP/HEE5ZnZdj6kA1v2bKFrj9zD9Wtw1+fyYDp+rN9+/Y333zTWpVh12eyPXZ9pupGupv64x//OKvrT3t1EbYCKlOjPZVpIyPH4vQ777xTKpUOHjy4e/fuZ5555rHHHtu3b5/lKsPi9ObNmx988MHt27cbb6kXNA7pghCL04888sjw8LDlKqOL03WD0IKuT6Mg9MGTsU5lqtUqZWX4IES31FQU0plbal2miu4Tfv3rX2/fvv2hhx6yXGVY4jOXyzWK0x24T+AzVRSnH3vssa1bt1quMro4zd8ntBen21gfdp9w5MiR8fFxdn0eGho6cuSIVSqz9r5BltXTXZ/nsvXm3E0lHqhMjTZUhrVzbj0jx+L022+/TTeLzz//PMXpoaGhvXv3WqIyN37vp7uff4l9TvibxZGREYrT7BzBwt0s6oIQXWRZENq8efPOnTstUZlU4qd7Xhij7LcNg9D27du3bt26adOmHTt2WKUye14Ym5ycrHuz2LEgpBnyeQcPHuTj9KZNm6xSmY2rHpycnLRbPo/uo2RZpjidy+WsUpn7Vz1EtwrGfN7Y2FjH8nn8dvbhw4f37dvHrs+bN2/O5XKvv/66JSqTW/0w3Sqw6zO7T9Cd85rV9dnRm0o8UJkas1KZ+dpUoji9devWwcHB+++/f/fu3R1WmTt/lB3bfWBycnLbtm1r167VxWmWtOzkphLFaWMQ2rhxoyRJHVYZWp9qtbpr165169bpglAnS2R0N4vGIDQwMCBJUudVZmj9Tn59Gm0qdaBOs1E+j1+izqvM1vWPV6vVycnJNWvW6PJ5HS6R4eP0oUOHxsbGWD6P4jStT4dVJr101d7dRVofYz6vYyUyjTb9+evz+vXrO68yy5OrX9r9yuTkpCRJuk3/uVyf2whhdgYqU6N1lZnLphK7WeSTlps2bRoYGFi/fv3u3btfKOzpgMr8/ObNP01tenn01cnJyUceeWT16tXGpCXrC8I2lRY6TpsHoXXr1j322GMdU5mfzazPrl27aH2MxR+2CkK0Ph1TmZ+lNu0fPTQ5OTk5OfnYY4+ZBCF2s7hAi6PV21SiJWL5vPvvv5+WqGMq8283PbB/9BBJDJUQGYs/OnbkTZfP08XpTZs2UZxet27d5ORkZ1Tm324aZOuzbdu2devWWZjPM9n0Z9dnKvmfnJzsjMr8/KbNj+Se3ae8ytan0fXZs5tKPFCZGi2qTBuDtXRxmk9a8nF67dq1jz76aLVaXferzQuhMqvS21akHzkwdviVva9NTk6+8MILDz/88OrVq1lS15IKROOmEhV/GIMQW5+19w0ukMrw68Mkr24Q6mQF4vHjx+tWIPI3i7Q+q1evnpyczGY2LZDKrEhv2775hVde+tD6GIMQqxDv5KYSi9OsSJzP57Elmpyc3P38SwukMivS2351+8NsffjPV91NJUvyebriD3b9ofXZtWvX7pG9S69OL4TKrExv+9Wyhw+89BoZjG59Gm0qdaw4z7ippLs+Z7PZXbt2VavV9SuGFkJlZtbnMK0Pfb5YMo9dn1988cW5bPq3URdhf6AyNZqqTBsZOb5hQ93iDz4OUen+tm3bXnjhhWq1OpiVhtbvbFtlNtzz1Pq7n3zqwdGnHtwzvu91+myQvqxatWrVqlVr1qzhTyrp4nQnN5UaVSDqghCtz6OPPjqzPo9tWb/zzmS2PZXZcM9T6+9+at1PHn/qQWV83+sHx15n4Ue3PiZByNoKRF0QovVZvXo1rc8D2Ue3rNtxx9I1bavMwN1Prf/JE8b1oSVas2ZN3QrETgYhreV8HnXj4NdnU3bb5nU77li6um2VGbj7qfV3m61Po8Nc1hZ/1M3nGd8/o7v2b14nLV+6qm2VmVmf0fF9rx/c12R9LMnn6TaV+Ouz8T5Btz7VanXzOmnr+sfbVpmBuz+4RL+678j4zPqwSzSTPN31eS4nSV22qcQDlalhrjJtZ+TqbsE+++yzO3bsyOfz9GnZsGEDfWAI+sDs2rVr165dk5OT1Wp1/+ih4l5VGizs2Dyyc8sLjw/temLr7ie37n4qr8gPjsoPjr768huv7n/j0P43D+1/k6yFdka2zUAXDv50AGsQznrfdaCwt9ES1c1+0xKR0PBLRNcUfn2q1WpxVH1lr7p988jOzfz67Kmtz8v69eGXaM2aNSw226f3Hb8+JtnvjRs30gZlG+vz1GzWp1HboU7WVNVdH6PNDA8Pb9u2jWxmw4YNzPnY+mzbtu3D6zNR3KtKmws7PlifFz9Yn/yo/ODo8EN72foc2v+myfrYqvcdQyc0utMGtES6SxCtD3cJmpi5BD2/c2jXE0MvPtHu+mzYsMEmve+IRkfeduzYwW44Z7c+W154nNZn656ZSzStzxvm66O7RLPed8b2pG0skfs2lXigMjVMVKaNTSWibhB69tlnJUmqG4R00DWX3uXbWoCykfyngmIPQRdZWwUhrYVqVpMlmu36sEsGvz5siewZhMyPvBmD0DyuT6O3kK73na6mqpNLZBKEHn744bpBiIfdaq9Zs2b16tXzsj4sCPFx2pLed0Sj0wYmt1Lzsj6NLkEmve86UFNVd30aHXlj91GNrj9trE/TS/QC3Uq1HcKcgrNVRjcfe8WKFXP51+qqzFwGa9F1luL0u+++e/To0bfeeuvw4cPj4+Mvv/zySy+9tHfv3tHRUaUjjI6Ojo6OvvTSS2NjY/v37z948OBrr73GDIYiUOcHRvJL9Lvf/e7o0aNHjhx57bXXDh482OElGh0d3bt3L63PK6+8olsfq8Yq6dbnrbfeOnLkyKFDh1555RVL3kK0RPv373/llVcOHTpkXKIOj8WhOMSvD32+XnnllbGxMQvXh94/NDVdtz6dWRyTJWKfrw4vkXF9SqXS0aNHyYCtWh/6fFUqlXfffVe3Ph1+/9AS1b1Es5uENpbIxZtKPA5WmWPHjnV3d/f395OiTkxMLFq0iH3bBkaVWbjBWicsYn5fxYKC9THBksVx0BJhfZqC9THHqvWZ3yVy96YSj4NVZnBwcPHixUePHuUfEQRhfHy8vX9QpzILlJFzxydkQcH6mGPV+jhlibA+TcHimGDJ4izEErl+U4nHqSqjS8kQlJhpe5uJqcxcNpUAAAAAC/FgCHOqytS1lrp+0zqkMgu3qQQAAAAsKN7ZVOJxtsoMDw/zD85WZZY1hmQWAAAAcAqe2lTigcoAAAAAbuD222/3zqYSj7NVZn43mJ555hl6NwyABmB9zMH6mIP1MQfrYw7WxwRaHE9tKvG4UGXm0l2G3g1zfnauBetjDtbHHKyPOVgfc7A+Jnh8cZyqMiYnmHS7TrPC4++GpmB9zMH6mIP1MQfrYw7WxwSPL45TVUbTtL6+PmNfGd0js8Xj74amYH3MwfqYg/UxB+tjDtbHBI8vjoNVRtfed45NZQiPvxuagvUxB+tjDtbHHKyPOVgfEzy+OA5WGW1mm4nNYGq7zy8AAAAAHIqzVQYAAAAAHgcqAwAAAAAHA5UBAAAAgIOBygAAAADAwUBlAAAAAOBgoDIAAAAAcDBQGQAAAAA4GKgMAAAAABwMVAYAAAAADgYqAwAAAAAHA5WxC8VisVQqWf0sbIqqqqIoZjIZq5+IfZFluVwuW/0sbEq5XM5ms/h8AeBWoDK2IJvNCoJQKBSsfiI2pVKphMPhcDhcqVSsfi52JJlMCoIAlWkEfb7y+bzVTwQAsCBAZexCKpXq7e1VVdXqJ2JTYDPmxGKxQCAAm2lEPp/v6uqSJMnqJ2I7stlsKpXCO6cRxWLR6qcAmgOVsRGwGXNgM+bAZsyRJAk2YyQUCmWzWaufhR1RFEUQBLavHQqFEomEtU8JNAIqYy9gM3UpFoukL7AZc2AzdWELApvRIUlSLpdj36qqKssyrj+Mrq4uWZY1TatUKvhk2RmojMVUKpVUKhWPx9kjsBkdiURCEARFUehb2AxPqVSKx+PJZJI9ApvhqVQqwWAwFAqxR2AzDPKYUqnEEjOpVApvHk3TWIV4JBKh+6hkMollsTNQGetJp9M+n4+/tsJmiHw+n0qlSqVSOBzmFwQ2wxOLxbq6upjqabCZGWRZLhQKkiT5fD5+D8XLNlMqlRKJhKIoLB+jKEosFtM0rVKpJBIJj79tJEnq7e1lmapkMlksFpnHlMtlWZb5zxqwCVAZK+nt7U2lUpqmZbNZ2IyRWCxGEahSqUSjUdgMj6qq7D0Tj8dhM0bY+sBmGKqqBgIBv99PJSCqqtIlCIkHRiwWY5eaXC4Xi8XK5XK5XE6lUl1dXYIg+Hw+2IzdgMpYhqIodBEhYDOVSkWSpFQqRYfSFUXh9020D19iNM/bTD6f171bYDOKolBlg6Zp2WyWP30Nm2HkcrlAIBAIBNglCB6jg11qRFEsl8uiKPb09IRCoWQymc1mZVmuVCqiKKbTaW9efGwIVKZzZLPZ3t5eQRByuZyiKD09PbpGFx63GVVV0+l0NBoNBoOKokQikUgkovsdL9sMyQrdEVIY1vV887jNiKIYDod9Pl8mk8nlcj09PTpNgc1oM/Ux9MHp6uoql8vkMZIkhUIhtLZixGIxei+Rvhg/RH6/31PvHJsDlek0iqLkcjlRFGOxmCiKup963GYIRVHy+XyhUAgEAvRIqVSSZZkaPHjZZjRNKxQK2WyWbqyNV1KP24ymaZVKJZ1OS5IUjUb5zxe9echm+LbRnrIZVh9D+0rhcDgQCFA+JpPJBINBTdMqlUo2m41EIrFYzDvbKKVSSRTFUCgUj8fpSkIfnEbXXlmWWf4P2AGoTKdRFIWusKIo0sGlXC4XiUR6e3vT6bQ205mUv3f0lM2Qx2iaVi6XfT6fqqrxeNzn8wmCEAqFKA8Ri8V6enqMZ5qsfN6dgkWjaDSayWQo8IRCoZ6eHnrc4zaTy+XIS9LpdCKR4N8/VNxKNsPv7ZLNuD4y6TxG07RyuRwKheiNkUwmRVEsFAqiKCYSiUAgEIvFXL8mjFQqlUqlEomE3++XZZl2lGRZ1t04EXU9xiO3UrYFKtNRmMdomiZJUk9PT29vr9/vTyQS2WyWhR9jn/V4PM5SFC6GeYymacVi0efz9fb2JhIJY947FovRTSRRKpW80Jme7wIiimIgEOjq6goEAqlUKpfLsbakZDP89dcj3b2Yx2ials1me3p6enp64vG4JEm825HN8P1U6BByp59uB5Ekie6U+DrfcDhM7wo6sk73CZVKhQpdLX2+VkL1Mb29veQrsVgsGo2yn9b1GEmSPHIrZVugMp2D95hcLhcMBpnvl0ol3XZsNpvlk9663iquRFEUyvyXSqVkMplIJHp6eig8K4oSjUb52KNpGu83sVhMEAT+Vtt9MI+hkkO/3x8Ohyn8qKqqa9hKh9jpz5VKJRQK+Xy+jj/ljsI+MvT+CYfDrJ1MPp/nWzdpmiZJEjM/Wh9BEFw8b7JQKFQqFVVVo9FopVKh+phwOJxKpegMNovE0WiULkrlcjmdTlN5n9/v90jWgTxG07RgMMia4+VyOTqCYPSYYrEYjUZ1eXTQeaAyHYLqWDVNk2WZiuzYI5qmpVIpQRDqpnMrlUo8HqcTgC67mujStuQxsixTWaKmab29vfQjuoOsu0tSLpfD4XAsFksmky4uWqSzXZqmZbPZZDKpKEo2m6X7bG2mtUzdLUjaRBAEwd1ZB0VR2P5sJpOh/h9MX4ybtgw6nBwKhYw15m6FnVcKhUKqqiaTyUwmQ5++eDyuKAodPA6Hw8lkknZejFV9riSdTrMrTCgUYhfkcDhMpzSi0Wg6naYdqFQqFQwGBUHo7e1NJpMu9mBHAJVZKFgpjA4Wb8hp2OPGEgcimUzqshHuIJ/PN80z8VtIjWxGlmX3XUTIX/nqVPY4e7HpdJrfUKu7qU833N6peODJZrN8ADYeX9JmaoTd9/4xgT93HY/HqV1ePB4nffH7/Z7dWorH4/zkyGAwyJaC9puo1ooO/KfTaVEUqQejNU8XfBiozEKhKEpXV5dJ1pHOoZRKJXYlbWQzbsX89ZbL5Xg8nsvlmMmZ5GbcRzabNX8zUB/SYrHIVqOuzXgWURQlScrn8+zzVddmPAXfz1eWZUonUP9J6pLinc9XKBQyP/bI30dJkhSPx3t6ejry1EA7QGUWEHObSSQSlJnQlR92dXV5x/RNAjaVPtDIAr7sg662XgjY5jZDJ5gEQeBvJb1mM8VisdH4w1gsVvfotZdtJp1Os7eTJEnBYJAKQVhVuEfuFkjpTDyG78/JOvF459C+E4HKLCwmNkPXDmokw4erVCqlay3jbhoFbCp9oPMU/LWVrrYeCdiNFoe2A7QZd+G3SOgR3m9cTKNz5rSNos24C/9pokc8UvzRCoFAQLeTGwwGXXweh6rmzesO2bYjf2YwFou5+2CBo4HKLBR0XkBrYDOqqrJCBzo1ykcjshl3h2pJklg4qRuw+UIQdmqUIJsxlpK4CRr7ojVYnFwux94eunPp2kzfnU49085RqVRYp0RtpqKobv6An/lH7sJ/vugRdyceNE2jkdexWMwkbFNijyZKsip7F593q1QqdGjL/NdIWXiP0WZ6zyzkswPtA5VZECqVCvWYom+NNqNLulD9Hf+I6+8adV1WdQG7UqnwkaZUKulyV7pfcBnlcrmnp4e9YYw2w1fy0ptN58rscJNrKBaLkUiE5vlRwt9kbJDO/OLxOPswEu4rhTbe+aiq2jR5SX20NU2LxWK05xKLxdzahYheHTM2k18rFotUaMU/DpWxM1CZhYKuI+ytb143UyqVXHkbbY65zehIpVLuTsPooCldLS6OoijuPmvNoJ01mozTustWKhUXf77IZY2HybPZbOuZ3VgsRtNC3Hqei/aV6CahaS9NSZJ0s2w1TfPsYUBHAJWZB0qlEruq0rBZCjmqqvr9/hZtJhKJuLW+gc5q0Z9VVeV72bVuM/l83q23RHy8oZfJtiZbtxmPqIz24ePE9HZqJYUQiUTcGqS1etMYZuUxmqZFIhEXpzn5+phkMtleDyHdNi6wFVCZuSLLss/n4wtf+FR2uVymvvL0rYnNpFIpVx5corqWUChE1xFSPf4XWrQZmpvdkafcUURRFASBP1DNr0/rNsP3Vncxun2lbDbbYg043/7YlfA2M1uP0Vz9/qF9JVYfQ7vVNM6CFCeRSIRmMCZjiEKh4MpNN9cAlZkHWH8UNt9E0zRZlun2ukWbcfGllo17LBaL7IXT/TR924rNqKrqylaB1NWDjuHwoy0oPUMPtmIzrkxZlUolPlVJMYl9TNjEJeMRdFVVdaWdrvRgHWQzkUjE6DG9vb0mR6zL5XKjEO500um0MeEUj8e7urr49wxdXmjUXd1bykYF5sAmQGXmB7IZXfdeFl1asRl397ogm+EnuciyrKuDNrcZd9f50qFiPtzGYjG2PmQzfObPaDPuO72vKAq/F0n3CVSsUCwWafoH+2WdzVB/Rd5mXNl5slAoJJNJ/nMUi8V0O01EOBw2+fgUCgW37m7TKAbdg7Ish0KhVCrVYk8HRVFceR/lJqAyc4LNeaFJQOyDYRzvRzbDUpRNewG7g0KhQANmVVXNZDKUm6lUKvwE7EKhQDGJbIbdElHAdmumSpsZU0f6QnW77L5ZdwpUM7xhmvYCdgf8LidZ0gAAIABJREFU7CT+3oDSD7pDSTqbURSFZs538gl3GLI99hopDWysm2EjEr1GNpttdI31+/2aprVoM67c+ncZUJk5kU6naaAu7QvQB4PPNxSLRUEQ6OhNuVzmR5zk83nXN4+pVCp+v5/dOLK6GT5OBwIBtiw0ZZP9yO/368KVy6CtJbavRLkZflYD9YNm48H5wkOaWuyyCaNGKDCn02k+JlGDGV0eVDPYTG9vb905aG4iEomwqMxeOG8zjTzGfMvJBdA49EbGT8OntJZtBtgcqMxcCQQC/PU0kUjwHVBofDH7OPGBh5pTuT4xk8/nQ6EQ+5byNGz6iSiKpVKpbq/0ZDIpCIK75xVTBSK/r0S5PVoKKnHlG9ry7x+al+6F+0XdXGvWJY8yVbrNFNbsOJlMujtUEywxowvGZDMm+0rmW05OJ5fLMVNhl19qGMh+gb2jYDMuACozV/hDwrSvxD487ByBcTuAitHYsW13w5qgU/qBVQGz+0Xj5BcaPFsul926hc+gUVz0Z9pXIncplUrsqI5xdEMsFqOzTi6ORgR9pvjZSfyeEZ0f1NUJJZNJ8yjuMiKRSN2iZrqtqlsP7votJ90omK6urnw+z99zqqrKv5FgM04HKjMPUBKbr4+hyQN8PyVd5YfrIzQPpV744znUsoyfTFupVEKhkItPhDaClEUzTHvRbT6SzdBylctlF5cQ8aiqyk/18/l8yWTS2BdbN/dD0zR3x2kdkiTxiU+CZMVYN6N5wGOMJBIJms/AHqGJkvzvkM144d7SlUBlZo2iKLqej6Io6up8s9lsIpHQab5uK8qtZLPZUCjEu1qpVMrn8/yNYyqVKhaLrAqYHozH4y5uycrgxwMRoijKssw8xrivRHR1dXmq37ERVjejezwSibh+0IcJdGPAbz7ysqKzGbd6DA2cCoVCdVtSUc04nxrPZDLGNxLV1njqPtM1QGVmTSgUojo7hqqqfHUq21fik5apVEoQBC+oDGWkeLErl8vsBoguK7QmbKepUqmk0+lEIuH6Ik1N0wRB0CWfJEliV1W+BRxvM7FYTBCEpg3XXYCiKKFQqO6OCR1K1727NE3L5XIezOfxxGIxVjWVTqd1ssJsxq0eo324TxUPm5GucXUzhUIhn8/XrVPkVxI4CKhMc1RVZS6fy+UymUxvby/vLsVikbVRDwaDfLwhmykWi4qiVCoVV+4L0FhdqlfI5/OKovCVDTzGmhhmM269wmqapigKu88TRZG2Gvmcf6FQoFtqSZL8fj9/W0k2o6oq9Vp03yqVSiWqi2KPyLLM5+p4IpEIvdOMruyduQ2CIBjXh52aLJfLdQs+JElydxF0IzXRQTZDzcexl+QmoDLNoTQDtYOkgE2jIuueEzZW+OoSm+5DlmUaVpzJZNjLNLEZYxFr3RNMriEUClH+XxRFWp+6R2+IeDyu25c07jS5Cfq/z14ytZ2t6zF0VIe22IzvLncf2mdQ/6q662O++ejKfEyxWIxGo3RZbr2FXTKZNJYWAacDlWlOKpWKxWKUPGAPtmEzbi2Pl2U5Go0ao0sjm9HqHckJh8OubL2vaRr1FeUHi2qmNmM8TMGf0HYldIJaURTeYwqFAl+UViwW0+k0S/7r3l2ubIWXyWQCgQBtTFO360aep5lWOrvSYzSuhzhl9crlsizLTYdXJxIJt15qvAxUpjk008ToLrOymXQ67crdJU3TRFFk7XrnYjNuVb1gMMhauvFLYWIzyWSStxnjaQv3QYe2+IrL3t5e8y0DSZLoWIpb53NpmlYqlSgrrPO81nGrxxD5fD4QCNAmPqWHzQvAqZNTU90BjgMq0xwmK7OymUwm09XV1aGnaCl8lG3dZuiOyn2Tg3TwJc/GaRUmNhOLxfjevu6G8g18r94Wp974/f54PF4qldzqwQQdSiePoTm1LdqJWz2GlJf2lehKoqqqKIr5fJ4f5WaEeu24vke2B4HKmEFHk/jDFLOyGRefN2HXAuOZ81nZzEI/T2spFAqhUIi/BZyVzbje8wh+34RsJp/Ps88OzQYxxuNyuRyJRLxwKlC3r0QtUlp5b7iyg2KlUgkEApFIhK+PoUI0VjtvYjPFYtHFl2UvA5XRk8vl+ItjJpPRtRNtZDNeOEisaVomk+np6eE3AnSDb7TGNuP6U47lcjmbzfIpbuPiNLKZusePXYaqqrrzSuVyORqN8lIbiUTY4lAUDwQCxlrXXC5Hb0KX7dvqXiZl9diDVDmezWaNPY51ZLNZt37c6PPCRpowj1FVlbb1yWbcuucI6gKV0ROLxViZCzVBoZykuc3QNq0XeivRwVdW5kIr09RmisWiz+dzfcGH7jQW7QUYE1dGmxFF0efzue8eWodufWgoOu8i/Mh0lo2gt1yjkztugs4H8C8zmUzS+lDvJX64m+6ixP/U3VAfJvoEVSqVVCoVjUZTqRSbu6SZVukBVwKVqUMikWB2T75ivHDwNkMjEgVBcPeGPYPZDIVqetBoM7lcjq4m1HgmHo97IbXLR2s2Etx4KIm3GSoS90hlFb8+wWBQtya6fAwL6vSWC4VC7rY9uqowaeMLn4PBoO5MvvGi5IWxbmxfia7PlI8hBZQkiaqAqX48kUhQfl2WZTqAretCDtwEVKY+9Nngswh038wuHLIsk8HEYjFXJrrNodDS09PDrq2yLPM2UyqVdFMAvQM7I8q3+tDlZiRJYjZD7x93B2keWh/+iB/lZtjGbt1Tx7R94OIWO4Sqqn6/PxwOFwoFfotElw0ldDbDOjx1+kl3ikb1Mfl8npplsE7rfL0znerPZDL83iVwGVCZ+qiqGgqF2NW2VCpRn1Z24YjFYnRuolHNr7tRFCWdTvObBRSHmM1kMhm6anjTZgqFAh94aG4Xn5uhRvtkMx6crJRKpUKhEFsffs4oTTA2loxQcAoEAm4tAWGwFBR7hOJ3U5uh9ledf8KdQZIkJrv5fN7v99PdYzabpVa/rFqR9xiPZMoBVKYOVCKjcY16afyhxl042OBDZjOu38hnsBnXbLMgm83yU517e3vpQXqk0RRAt0IFH/xOCnt7kM3Istzb28t+udEJJreSTCZVVWXrQ7XA9KNKpRKNRnWbceQx7M+df8IdhjbaAoEA3SPRBgr9iGyGVbwSdFGiXI6Lr0JsvgfBGlOR2haLRVol3flzXRk+cCtQGT2qqvJnkchm+A4f2WxWEARBENjnSrfD7W7K5TK/PhSQdHVCdEqWTzZQNzMvnC4m8aU/s50mfthhMpkUBIGpjKZpsizzs4vdDQ3zoz+znSbdG4PfqeQ9xgsoikIfHLKWWCxGg9PZL9BGmy7NWSqVXLyv1Ai+zSZNf6O1SiQSoVCIvW2MFyjgPqAymqZpoiiaXC6j0aiudS+NKeYryFRV1d0quQnzMVK5XE4QBD7vXSqVYrGYcXyxF1RPR6VSoRwV39eYKhP5X5Mkyd2znekgkvHxcrns8/mMFTBslIGnPEbTNP5TRjaje6toM+7rwU+TEWYzuVxOFMVSqSTLsiiK/F4bzTXzQj7Py0BlNE3TAoFAozhdqVR6enrYmaYOPzGbkEgkTF57IBDI5XLGXXzvQMNf6i6Roig9PT3unpfZFDYz0vijTCZDBZt1bYbGuHboWdoSURQFQTBW43mhZqhFyGYa9QOkYgDPXrq9A1Tmg8xko5+KohgIBDQPDLjmkWWZ5Zz4ec7GG8F8Pk83iHVrEt0Klb/4fL6enh5Jkmi+Ut33RiQSoUIZz9oM24KsW/odCAToHEojm6krQB6B7qP4uhlGKpXyWr7KhFgsFo1GqTm7bo4KPMYjeFFlqF8tv8OqaZooisYMf6lU6urqYmXzHrEZmrhGgYd5DJ3z1I1hq1Qqfr+fHbXwjs3QC6RZzblcjnrnGH+tUCiww7HetBlzj8nn84IgUHah0fp48HgXg1Iy5XKZ1c2wH0mS5OWVMULvIv4SDY/xFF5UGQrVhUKBeQxNHqbhL/xv0tkK/ipMHxXX91lKJBLRaJR5DPX5yGQyuqMlBL8adU9YuIlsNqt7n/BZPV3iqlgsJpNJ9lMWrT1S5WDuMQQdZeJ/32u2Z0IymWQHDnQ24+K5BO3B2nqxlmDwGE/hRZXRNC2RSITDYeYxyWSyXC5TWUOhUKDutI2up/F43K2hmmo+VFUl2+M9hp0lpkhjMgJGVVVBENx6ESkWi729vezOj/eYQCDQtGNvpVIJBoMeOaxESQW+PwohSVKjERZUE+36ARftQTZDSeJ0Ou0RIW4RSZKYMVM3PLdegkBdvKUyLBKXSiW6wjKPoV+gnCR1w2v0j9Bk2s484Q4jyzK7J47H46qqMo+hXhd0EjsUCjUaQUDTAd197rpcLodCITo+zV8u6SSXecauUqmEQiG/37/wT9N6KPTqqlapyVCjTm6kMqxpE9BBZ5eKxaKLP1/tUalUUCTuZdwZkhvBV7nH43FZlsPhcLlcliSJteGnzGTdlEypVIpGo5FIxJWhSGd1hUKBZgNRWWsqlQoGg+l0WpblUChU9+Qw/QvUedP11xTqncPnV6hIk39EtwiFQiEajdJbqEPP0mp0NsM8pm5GoVQqhcNhWqKOP1MHUC6XacMO+QYjpVLJWMwHvIOHVCaRSOi6QNK4E3YQgKpncrlcOp0OBoPGq62LpyxRmQLrsiXLMg1RkmW5p6eHhWRZlmVZptQCJbrz+bwHc920ryRJUldXVygUYm8MURT5bor8XCHNMz3UaWwF+6wxmwmHwyYeA8yh/Ggul+PXFjBUVWUjmYAH8YrKiKIYDofp1lBRlFAoRI1AqHUmuTw/qywej9OtIT+c1q1UKpVIJFIoFPx+vyRJlUqF6uZoNeg4eqVSIY+hv1Iul3t7ezOZTCwW81qum6+PKZVKwWCQjmRrM3VCvLKkUinvtGFl24uCIPAOx2ymp6cHwQYAMO94QmWSyaTf7y8Wi2QzpDXhcJjKGqg+JpPJ5HI56hrJEg+RSMT1cYh2hZLJJC2I3++Px+NU3Mr2SqLRaDgcpmHg1EZTVVVVVX0+n9dOhNbtQkSzCMiP+TyfNtPtN5VKuT6El0olv99PJUTG/GXduhkAAJgX3K8yiUSiVCpJkkQ209vbS3WsZDMUYOLxOO0L5PN56spVLpeNx27dB+VjKIuQSqXC4XAymaREFA2WIpuhY9iUnaJpL9QdnIYjeifdrfMYGjtKq0ftuXw+Hw32S6VSqVSK3ks0ccn19Q20f2RyQhg2AwBYIFyuMoqisD0RKjksFArhcJjukslm8vl8MpkMhUJ8wSYFrUKh4J2UOCWiKDfD20wikchkMsVikW+ow1rOBINBLyRmVFXVvUO0mQ5v/Mun4VNUQEOkUikv9P+gGavGd4IkSfzQeNgMAGAhcLnKMOgGWhTF3t5e2mlKJBJ08pNyM6VSiVU8sJtvKn3wQlV8Pp+nw1x0foQkJp1O09YJhfB8Pu/3+2lSMRtloDuz42JSqRRr3atpmqIodFZL12KHTnhZ9BwtIxKJGCcM0M0DFfwabYYvpgEAgLngFZVhHWXS6XQoFKL2vjTnj+000SSdTCZDcZqSEz6fz8UHlxislyj1cMvn86Q1yWSSr5uhnsisL3gkEjGfNOkyUqkUiQt5DHuQz1fJsuzBs8T0UeIfYeeuaYy8zmai0ah33jYAgIXGbSrD90HXwWwmGo1SHKIiDyrMpEttNBplqW+qAu7YM+8ApVKJqpvr/pTZDG2msMepLphsplgsshyMFwzPCNmMLhEVj8cpX6VpmizLHmxW6/P5+PcMlYQzfTHaDAAAzCOuUhl+Ol1dyGaKxSK/VU+Vm3Qwx92XWsq48P3ZyuUy37KW6odisVgsFiNTYX3z+Cpgj0M2o+vqGwwGyWAkSfLCyGKahc6+DQaDPp+PfySfz/OfJrIZD0oeAKADuEplNE2LRCLxeJx9S6dy+Esq2QxTGXYCRdM0L9gM9dFhCRWd1WncSD/Kb/H9f4vFojEh4VYo/9So+x+lqdjKUMU0pSXYBqWLoTcJn4ahmioTU6F5TF6oEAcAdB63qQxV71Koph0TY9FuKpWi0QS8x2iaJopiLBbjTciViKJIFZflcjkSiRhrVFluhvcY0hpFUQKBQKefsRXQsBuT7n/BYJBqYqiKnJ1vcn1Kpu6863K53NPTIwhC3eYF9Kn0+/3uvk8AAFiF21RG0zRRFNPpNPX5zmQydS+gVKrJ3z2Lokhh23231BSP2V4SndsqlUrU55smK+n+CrMZ9i3TGpdFo1KpFI/HjdmCTCZj3sWY8lvG3zEfJ+l06noMIcsy9fnV5e2oi7TP5/PCSUAAgCU4XmVSqRSltemsLB2rZn3wNE2LRCJ1m1iwKmCN8xj3QceyNE1TFEUQBMoZJBIJVjGjqmpPT4+xwIjZjG6byWXQy+zt7eXzc7lcrpVpDPl83iM5KsLEYwiaP0otAen4WygUonkF8BgAwMLheJVRFCUSiVCzE9YkhvaJKPrStKC6ee9EIhEIBFzsMUQsFisUCpSS6erqYnM0WSFILperm7ui/A07m+NW6OQas5kWPYZg4y+8AJXu6pIulUqFfdY0TVNVlWaGM/ifAgDAQuB4ldE0LZ1OU7KBNuzD4TCNCqLaDk3T8vl8o6a9sViM5WbcSqFQYAVAiUSiq6tLFMVoNEqtaSkSh0KhukUeVG/khYMnNGRAFEWjx4RCIeMeHJHL5TxSB61pWi6XEwSB35mlPI3P5zNuy9K41o4/RwCAF3G8ymSzWdY2NJvNUl1qOBym4J1Opyn3EAgEGk1TisViLh60RDl/NmVJVVXKzUQikVKpRBmsRCJBcxDr/gvlctmV60NNEflwGwqFdDtNhK6sSvePuL5OnGas0p9pQAEtCPMYr41GBwDYDcerjCRJVH1J+ybaTDd96scqimI+nw8Gg5R9afSPuK+UlbIFFICpRW8ymWTrk0wmZVmmeZmqqkqSRH1BqBCY/hFZlt1d35BIJPjjwbSvRLkZ3bk28+yCu1dJ07RoNMr3vGY2EwqF4DEAADvgSJXJZDJ08pPKD6lFOv1ZVdVsNst6jFIQqlQq6XS6q6uLnCaVSkWjUb/f79YEeLFYFEUxEolQooUKZShCK4oSDodpu0QURT5mJ5PJrq4uWliiUV9gd1AqlXw+H5WE8/UxvM008phQKEQVWh18vpZBLWH4TUayGVZFzkOtor1TPwQAsAOOVBmiWCwWCoVisZjP5yk3k8lk6FxSIBBIp9OKoiiKwq6qqVQqFovJspxOp9m5Jy9AuRayGUrV0Kku0j42MEhRFNZjhjZfXB+qaQ6Xsc6XbIbvg6zDZMvJfVQqlZ6eHt0wMn6niT1ILaHrbtIBAMDC4WCVYYiiWCqVyGbowsryMbrGvt6p0OShFjuaplEptKZpbLOJMjG0RaIbveQFKDFTtwVtIBBo5CtNt5zcByVmdLXPOpuBxwAArMINKkNjrjVNk2WZ0g+UaUilUrIss5PYoih6U2U0Tctms3yjPNIXOoWez+epLrhcLntNZTRNSyQSxncFyUosFjPajAc9RptJzBiPATKbyefz8BgAgFU4VWXK5XImk4nH44lEolQq5fN5qpWhw7Q9PT2RSISuqsVisaurq1gsZrPZRkdqXYkoitSvjDwvHA6Xy+V4PK6qKjVm5bfeqPKDnzTpEYrFoq4enJcVnc1402MISswYi2NY3Qw8BgBgFU5VGU3TCoVCOp2ORCK0QRAOh7PZLAlNoVDghyYmEol4PJ5MJt1djUhlQJIk8bfOiqLQmlCJDIvEVDlEf6a9OTrT1Okn3SnYcS3jj/gegEZZYTbjBY8pl8vhcJhuD3Q/apSY0TQtm80Gg0F4DADAKhysMjr4qlVN0xKJBG0zKYpCR5Fd2f8jmUxGo1HaNqIx4NQzvu4vx+Nx1iGGIpOqqvl8PhwOkxG6uM5Xd1yLJ5VK0dwGSZLqHi2OxWJ0vH9Bn6EdKBQKdITN5/MZhaZRYgYAAKzFSSqTTqdDoZDJzV8ikWBbSDSJiQ7pyLJM0xM79EQ7SCqVYoqmKAodn26UfOLHhmvc3E361mUpmVKpxByF9Ryix3Wd8YrFovmxcy/kYxiVSiWTyfT29tK2EZ10Yz9qlJgBAAALcZLKRKNRQRBMWnLJsuzz+VggTyQSLERVKhVXJsBZAVCxWKTyVVVVaYxfNBrVdW+rVCqCINCYKvrNcDhswZPuFD09PbQ+yWSSOh1rmpbP53VdUjTTcdae8hiebDbr9/t1QoPEDADAhthXZXTJbQpF2WzWpMEojbvr7e2lv5vP511f50sFLqqqRqPRSqWSzWbpSA7BDxygoYnxeLynp4ftQLm7zjeVSlEaT1GUeDxOS5RMJoPBYIstej3rMQya/s2Eplgs9vT0eGoeOADA/thRZRRFYW1YCXZLrWlaI5spFAr5fJ5OFNOESFVV3Xr6OpvNplKpSqWSz+dpMoOxTpN+h98doGRMsVj0+XwU193dJzCfz/NvAPIYOvvWSooOHsOQJCkUCpHQUDGNK8dyAQAcih1VRtM06rVKf+bjMWGem6EqGSqUqdv9zAWEQiEqbUmn0729vdlsNhaL8fJHv+Pz+eqWNdAmSzqddutoAloQ/g3APEbjrM4EeIwRWZYjkQg1knHldi0AwKHYVGVYZ16jx2iaRvOcTWxGURQaiG3MVbgASZKYgmQymUgkwjaPZFlOJpOVSiWXy+VyOUEQvBlyEokEvfBcLlcsFpnHZLPZVtoA6vbmAE+xWHTlxwoA4FxsqjLFYjEejzfyGBoqZJ6bcSuSJPn9fnrVsiyzut1UKiWKIlVlsqFCgUDAZeeSTKAj5Rqnv6IohsPhQCDA8jE0JNyt244AAOBNbKoymqaFw2ETj6FvvWYzkiRFo1FVVclmaEI4vfxUKiVJEg0VYhkF1lyHUS6X3XqSNplMhsPhZDJJw8/ZXlIsFqM/k+LQqCB3FwkBAICnsKnK8I1AGDqPYb/pEZuhBm7hcJhCMpXIKIpCNpNKpSjtHwwGab6mpmlUEcz+BVEUg8GgW1WGJlSoqloqlchm+PoYPsOXTqf9fj+N62rxKBMAAADbYjuVoXOzxj4fdT2GEEXR5/O5tYKVkCSJDpZXKpVwOByNRjOZDOVmyGZYzS9tzImiGI1Go9FoV1cXnUmmpmeubHnM4OtgGnkMDdGkyl/XLwgAAHgB26kM5RtYGzfCxGPK5XIymcxkMoIgeKQaURTFQCBAJ4qZzXR1dVFqShRFZnWyLJPKpFKpuokul8G2jcw9hv0CG2ph0fMFAAAwD9hOZTRNU1U1EAgwm2nqMfQjalHvesLhcDweL5fLwWBQkiQyv0AgEIlEaKdJkiS2aaIoirv7+eqg90mhUCCPKRQKNAmc/ZT3GPqzqqpdXV3IzQAAgHOxTGWo6Vaj8zXlcplsplwut+IxroSmBelSKbQylGkIBALFYrFcLpO70E5TLpdjf0WSJE+lHEhnA4EA/YGSVfQeq+sx9Hg+n0cnfgAAcC6WqUwqlTLfEqKY3dvbW3dcs+s9RtO0bDZLbYt1jzObyefz/EkcVVXT6TQL3pqmpdNpD/ZHoQ04+jPZDDvEZPQY9MEDAACnY43KUAhpOgCI5WZ0yuIFj9EFXR3MZthZaxpQpX04FREKhdy9SnWRZdnv97Nv2YLAYwAAwJVYoDIshBjPwTbKQPA24x2PkWU5lUo1CrdsZTTOYwjKzWQyGeybEGQzkUgEHgMAAO6j0yrDh5De3l5+bBD1fDP+Fd5mvOMx1GVfN1ZJB61MNBrlPYZa/SqKQnmIBX+61lEqlUKhUIu6pqubgccAAIBr6KjK8DmGcrnM13nwx4mNMJvxjsfQWG+K1ibDB2hlmPGwkQWuRJe0k2W5p6en6TYlg9XNwGMAAMBNdE5lqBiTgi6dS2I/ohgTCoUalYbQX/H7/ca6GTeh8xhN07LZLE0RMl8ZWlgXe0yxWAwGg/yRaUVR6FASb3JNkWWZH+wAAADABXRIZSilzwIP7zH5fL7Fxh6sW/8CPlHrMHoMU5NYLNaizXTs2XaYSqXC97JTFIX9ebavnXbfFuRZAgAAsIJOqAxfmqALPOl02ufzUYlMLBbr6uoy/6dUVXVTVkZVVWraa+IxRF2b4ZeCFtatWRlN07LZLO0lKYpCb5VGbyoAAACeYsFVxlhiyYpVg8Gg3++nbmaqqiaTyd7eXgrkHkGWZUEQ8vm8icfQ+CRtZggi39RYkiT+WxdPvdY0rVKpBINB2lfSNC2bzcJmAAAAaAutMjR5uFAohMNhKlCoVCq5XI667KdSKRobyUI4bSF5qot8IBCgdEtdj1EUJZ1O81W9NFOJKUs0GnX9ZCVGPB7nJ3ub20y5XE6lUul02sV6BwAAQFtQlVFVleYalkoln89H549CoVA8Hs/n83Q2JxgMshBO5PP53t5eGlycz+ddH4pEUaRaZjqclcvl4vF4JBKRZVlRFPI/URQlSQqHw6qqlkqlcDjc09OTSCQkSRJFsaurywt1rLQZFw6H+dJvE5tRVdXn87l4xw0AAADRobLfRCIRDAZ1D1IOJhQKsUdo+yCfz0ejUWEG/sy2+/j/27tDJld5KIzjSD4CEomsrKysrEQikZV1SD4CMhKJjIysRCKRlUhkrjizGYbu9t339hYm8P8p2kXQNTyTnJwzDEMURXIt6zF938uW0zSgVFU1fSt3XSe5UKKhLG5tmNZayr3HcfxlmlFKkWMAYA8WijJd17kXtjOrj5EcM46j7Entp1NtkiTSEM8dzpKJ1m6xSpZk1nq81WmtwzB0/5zfpJk4jskxALATy/WVkRe2+/hcH+Oyy6x73uZJvYsr4JV9pSzLZB3LGNM0TRiG7s0t20yrPe4ajDHTMZmv00xZluQYANiP5aKMlHrI9XN9jFSzWmvHcUzT9EUPle2RtShrrUwbkH0lrXUcx8YYmVTlrs/ncxAEz0tcmzedPGB/TjNSQrQNuYdEAAADyElEQVTaUwIAFrdclMmyTALK7XabbpfIvpKszdxut8vlsu3Kj6qqgiCYFb6469Pp5FZcoihyt6VpGkXR6XSqqsoYs6uo5/xnmknTlBwDAHuzXJQpy1Iu2rad1cfI93LkZJOHcbTWbgy4dAV8ngouXCvkuq4Ph4OkljzPoyjaT/HQCy/SDPtKALBPy0WZaXnHc32MtTbPc9eNfkvGcYyiSJKcjA1K0/SnX3q/3x+PhxxlKssyz/Pz+ay1vlwu++kf89q3aSZJEnIMAOzTopOxp/q+n47CLori9yOOvSOjNCXH2K8Vl59ulooZa62kGdk9mR5ZxyzNsB4DAHu2WpSx1rZtK+9ppVQcxxuu/xjHcbpsMI5jGIbu97Zte7lcXnQCvN/vm1yveodLM+QYANi5NaOMUEqFYbjJUt9hGNwJYaVUmqZKqaqqiqKQ/TU5cR0EwevhQXmebzjn/bW2baeV0QCAfVo5yjRNEwSB2ynYmLqup33b0jSV667rjsdjlmVFUSil7vd7URSzoZuO22/CDP18AQB23Sgjxb/PAw22QSnlipqNMX3fT/v+ZVnmsovslfzUFZCDS99SSu1qiDoA4CfrbzBtcuukaZqmaaQ+ZhxHmSQlQzTlBtdlR7oFyuSgb9/NHFwCAOCF9aPM9tR1nSSJUqrv+yRJZC7B4XCY7hPJZtO067GkmV1NbAAA4H1EmX9MJg9ILqmqqizLOI6VUvKNG+98u93KspwFFzfVeZ1HBwDAQ0SZf0kGXMv14/EIw7CqKikJmqYZY0zXdbN5zvarwvdwOOxtWiQAAH+NKPMRxpg8z/u+Px6PWmtJM9fr9Xg8RlHkmsRoraMokjQjA7GttS8azAAAgBmizEe4lieyEtO27TAM1+tVjjLJIo3cKWnGDcQGAAD/C1HmU1ya0Vq7jjL2q1Bmel6paZrZThMAAPgloswHuTSTJIl8IzlmGIbZ6WspoFnrOQEA8BdR5rMkzcjwSJdj5E9SF0yfNwAA3kGU+ThJM03TTHOMxBrpN8N5JQAA/hpRZgkymqCua/k4XZ7hvBIAAO8gyizE1c3MtpkAAMA7iDLLkTTjpi8BAID3EWUW5dZm1n4QAAA2giizNJlOsPZTAACwEUQZAADgMaIMAADwGFEGAAB4jCgDAAA8RpQBAAAeI8oAAACPEWUAAIDHiDIAAMBjRBkAAOAxogwAAPAYUQYAAHiMKAMAADxGlAEAAB4jygAAAI8RZQAAgMeIMgAAwGNEGQAA4DGiDAAA8BhRBgAAeIwoAwAAPEaUAQAAHvsDh7M1BUjtCwwAAAAASUVORK5CYII=
图2 临床Ⅰ~Ⅲ期肝癌药物的机制分布(top6)
处于临床Ⅰ~Ⅲ期的肝癌药物有77 个,从机制分布来看,临床研究阶段的肝癌药物最多的是蛋白激酶抑制剂,有17 个;其次是酪氨酸激酶抑制剂13 个;再次是血管生成抑制剂12 个,血管内皮生长因子拮抗剂10 个,抗生素类抗癌药物6 个,蒽环类药物5 个(图2)。
临床研究阶段肝癌药物的研发公司较为分散,但这些公司中美国的公司最多,有48 个,其次是日本的公司有25 个,再次是英国的公司有13 个。从3 个研发阶段来看,处于临床Ⅱ期的肝癌药物最多,有49 个;处于临床Ⅰ期的则为10 个。处于研发后期的肝癌药物有19 个(见表6),其中预注册的1 个,临床III 期的18 个。处于研发后期的肝癌药物主要为酪氨酸激酶抑制剂、蛋白激酶抑
制剂、血管生成抑制剂等。
(3)肝癌药物临床研究进展
刚结束的美国临床肿瘤学会2013 年年会(ASCO2013)对肝细胞癌有部分关注。因为晚期肝癌已经有了索拉非尼这个标准治疗方式,新发展的局部或全身治疗要么是跟索拉非尼联用的一线治疗,要么就是作为索拉非尼的二线治疗。具体研究包括一线治疗:使用阿霉素洗脱微球的TACE (DEB-TACE)+索拉非尼的Ⅱ期临床试验;一线治疗:索拉非尼 vs 索拉非尼+吉西他滨+奥沙利铂联用(GEMOX);一线治疗:索拉非尼+卡培他滨+奥沙利铂(SECOX);一线/二线治疗:TGF-β 抑制剂(LY2157299);二线治疗:PF-03446962(ALK-1 单抗)的Ⅰ期临床研究;标志物:VEGF及VEGFR 的基因多态性与索拉非尼治疗毒性及疗效的相关;一线治疗:Pexa-Vec(JX-594)与索拉非尼的序贯治疗;二线治疗:Regorafenib;二线治疗:Pexa-Vec 的溶瘤免疫治疗;一线治疗: Nintedanib 对索拉非尼的头对头临床试验;二线治疗:Tivantinib 的Ⅲ期临床试验。
3.肝癌药物研发管线分析和市场预测
(1)由于新药投放市场,肝癌市场前景看好
全球商业情报(GBI)调查发现2011 年,在主要的7 个市场(美国,英国,德国,法国,西班牙,意大利和日本),肝癌治疗在3.743 亿美元,从2004 年计,其复合年增长率为21.7%。增长主要由于患病人数的增加和每个病人治疗的年度费用增加,后者的增加时由于多吉美(索拉非尼)在美国和欧洲被批准上市。处于晚期的肝癌临床药物开发包括很多全新的药物和仿制药,它们对肝癌病人有效且安全。一旦这些药物进入市场,市场增长将会非常可观。预计到2018 年市场收入将达到6.443 美元,从2011 年计其复合年增长率达到8.1%。
(2)目前肝癌市场的竞争较弱。
目前肝癌市场的竞争较弱,只有5 种上市药物。多吉美只适用于晚期肝癌病人,而且使用多吉美治疗只能延长3 个月的存活期。一些化疗药物例如顺铂、阿霉素和长春新碱,作为没有被临床试验认可的药物治疗儿童肝癌。使用多吉美的花费大约为每月2770 美元。然而,使用多吉美治疗的直接费用(包括药物费用、医师费用和医院的费用)为每月5400 美元,因此在一些国家比如英国,这些费用不在报销范畴。很多无法承担这些费用的肝癌患者不用这个药物,结果使得肝癌市场中的竞争变得更弱。
(3)多个晚期临床进展的全新药物使得肝癌市场非常强劲。
肝癌药物生产线非常强劲,拥有100 多种处于不同研发阶段的小分子。这些小分子中大部分是全新的分子,既作用于新的受体并且有新的作用机制。临床晚期发展阶段有19 个化合物,其中有7 个血管生成抑制剂、蛋白激酶抑制剂,5 个酪氨酸酶抑制剂,3 个蒽环类抗肿瘤药,3 个抗代谢类肿瘤药,还有光敏剂,免疫增强剂、单克隆抗体等。目前有一些处于临床Ⅲ期研究的小分子,作为治疗肝癌的一线和二线药物,有可能在未来的两三年内影响竞争格局。礼来公司的一种单克隆抗体
ramucirumab(IMC-1121B),Celsion 公司的ThermoDox 预计将在2014 年投放市场;以及2015 年的PrevOnco 将会进一步推动市场。
(4)在有效性和安全性方面肝癌市场还存在很多未满足的需求。
在肝癌市场,有关有效性和安全性方面还有高度未满足的需求。被诊断患有肝癌的病人中有超过90%处于45 岁到85 岁之间。多吉美是FDA 批准的用于晚期肝癌患者的药物。然而,服用多吉美治疗的病人期中位存活期只比安慰剂组病人多三个月。此外,多吉美安全性低。服用多吉美的病人报告产生3 级和4 级不良反应的比例分别为39%和6%。因此,经评估,在肝癌市场中高度未满足的需求占56%或1.317亿美元。由于很多新药及仿制药预期将投放市场,大多数新药都是针对早期肝癌的,因此它们将被用于治疗那些目前没有治疗选择的病人。
参考文献:
1.GBI Research. Liver Cancer Therapeutics Market to 2018
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4.Katherine A. McGlynn1 and W. Thomas London.International Liver Cancer Incidence
5.NCI. http://www.cancer.gov/cancertopics/types/liver
6. Siegel R et al: Cancer statistics, 2012. CA Cancer J Clin 2012, 62:10-29.
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8.丁香园. ASCO2013:肝细胞癌临床研究结果大放送.
本部分载至《全球药物创新快讯》内部期刊,冒险转载。 求过十,参与超过10,会有后续不断更新专题。 看着就像那里面的资料 药物所的这个杂志对于研发很好用 不错,单抗药物还是一片空白
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