靶向蛋白- 蛋白相互作用治疗癌症
本帖最后由 dejunchem 于 2013-7-25 20:32 编辑关注人太少,我都懒的更新了.不过10回帖,类似专题性质的帖子,不再更新,需要找材料和排版还是挺麻烦的。
靶向蛋白- 蛋白相互作用治疗癌症
摘要:癌症基因组学、靶向治疗和肿瘤网络的出现不融合显著扩大了蛋白-蛋白相互作用网络在癌症治疗研究中的前景。广泛的生物学和临床研究促使蛋白质相互作用枢纽和节点的确认,这对获得和维持癌症基本的细胞转化特征是至关重要的。这种癌症驱动的蛋白-蛋白相互作用(PPI)已经成为了非常有希望的治疗靶点。随着PPI 调节物发现技术的进步和PPI 靶向制剂在临床的验证,靶向PPI 相互作用的接口作为一种抗癌策略已经实现。未来,基于基因组学的PPI靶点发现、PPI 相互作用特征、以PPI 为重点的化学库的设计和病人基因组亚群驱动的临床研究将有望加速下一代用于个性化精确医学的基于PPI 抗癌药物的发展。本文对介导癌症获得性特征的重要PPI 进行简要综述,突出靶向PPI 已知的挑战和有希望的临床结果,提炼出新的机遇。该文来自TIPS, online 29 May 2013 的《Targeting protein–protein interactions as an anticancer strategy》http://www.sciencedirect.com/science/article/pii/S0165614713000783
1.靶向PPI 研究的高涨热情
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SU0dFRMjhNqVQ+fvw4LCzM1dU1Nja2r68Pn75YLNb9+/fDw8MjIiJwWenk5ORHjx5tbm7iDwB9kIS9I0hEG/JIVyPdTFiQJHxPou14hhcyHQd9UhgiS7we0nm+Y6EABIIEAODFoL44GBGrDhcc53K5S0tLS0tLCwsLQqFQp9OJRKKlpaWJiYmZmZn5+XmpVIpXgt8rFos5HM7ExAR5iaIolUrF4/E4HA6Hw2Gz2XNzc/Pz85ubmyqVipz0QJCYvSNIk5+TPiaSfsdgMOBQO33+KWJHk7YjMg6nJc1TvCT6YmMUBAkAwMuCLkhkdmYj4DEe5u+laKVR0BfjZLimGH36ZTr0tgEIErN3BIloc37in3l9fZ3JZI6PjyuVSuJIvH9otVoWi9XW1jY2NoYLLJFyTZ2dnTU1NXV1dcPDwwqFAg9CUqvVT58+raure/jw4ePHj6empnBiNAgSAICXCGVWy8YkHkbiXsisvib9RGTyPH26Pbp9KYoic3cQQJCEPSVIcmWkVqvX1tYyMjIuXLgQHx/PZrNxWRy8b6nVag6Hc+3atU8++cTHx2diYgK/Bc8Bcvr06UOHDh07dszZ2ZnJZOJqrr29vaGhoSdPnvz8888PHDgQHBw8OjpqXm0OgSABAHgBvkKQJsEtRNMbecZAG6pBbynS307u0C37FR/g+8xeEyS+w2azi4qK3NzcDh48GBAQMDQ0hGMLlHEG0f7+fmdn5z/96U+2trajo6MIIT6fX1JSEhER4e/vf/v27YiICFdX17S0NJlMtrGxUVBQ4OHhkZycnJOTExYWdvr06cLCQly6EAQJAMDL4qsjnHgOBkTTG0kVpGcpEujtTlKemuRP0N9iME7igWiOhPPVnhIk+XUnJycLCwuDgoJcXFyCg4P7+vrI9ZTBYODz+UlJSa6uro6OjtbW1k+fPtVqtX19fY6OjufPn+/q6pJKpUtLS1FRUba2tpOTk+3t7QEBAYmJicvLyyqVamxszM7OLiQkZGJiQqlU4t0Op7ZSxqmS8X2hUMhkMmdnZ0lXAexwAAB8LfRIKWnhkStv+qsvcXPmQVpg7wiS/Kg6nU4mk0kkEiaTGR4eHhoaOjw8TCbLFovFTCbT398/Li4uKSnp/Pnz/f39CKGampp9+/b5+vrKZDKEkEqlKigosLOz6+jouHHjxuXLlxsbG3Ea2Pr6Op5otKqqSiaTkXYkdrBcLlcoFFKpVKlU8ni8trY2Doez48UdAADAjtAtRb/zLQnS8EVAkIQ9JUhsKaVSiVtsExMTcXFxMTExY2NjOBNVLpczGIzo6Oj09PSmpqaUlBQXF5eRkRGNRlNaWvrOO++EhISo1WqVSqVSqaqqqlxdXevr64OCgvz8/Hp7exUKBUVRW1tbpaWlAQEBubm5MpmMpL+KRKKhoaEnT57gyWWYTGZzc3NNTc3U1JRarSYdlpb+PwEA8Kpjcq7AD4m9oAW5a+wdQZrnKE9MTMTHx0dFRfX392M/8fn86OhoHx+f6enpra2tO3fuODo6Tk1NURRVVFT0wQcfBAYGKhQKhJBKpaqurvb09CwtLXVxcfHx8RkcHMRx1M3Nzerqaj8/v6ysLDy/Gt6uTCabmZkZHR0dHh4eGBgYGxt78uRJU1PTzMwMqQIMAADwtZgLkt68A4ftGntHkOZXQJOTk3FxcdHR0X19fVqtViqVlpeXOzs7u7u7t7S0MJnMK1euHDp0iMFgyGSyqqoq0oLEVFVVubm51dTU+Pn5eXp69vb24ujrxsZGRUVFQEBAQUHB9vY2RestxzV3cOKrRqPZ3Nzs7e2dm5sjgoTdGgCAr8VckCTXBkKsu8neESQpSI9/XZ1ONz4+Hh8fn5ycPDQ0pNfr19fXAwICDh065Ojo6O3t7eXldfjw4X379vn7+3M4nOrq6nfeecff318mkxkMBo1Gk5eXZ2Nj09/fn5iY6ObmVltbq1AocF3E9PT0wMDA2tparEzSAYkgixUAgJcKvf6XWq0WiURqtRrnOkgkEo1Go3hOlEqlUqmUSqUSiUShUJDpkTUaDUVLMwTQXhIkQgj/xnhgkEajefr0aWJiYmxsLA6xyuXy1tbW3Nzc4uLikpKSmzdv2tnZvf/++zhS2tLSsn//fg8PDzwsksfjJSYmOjg4sNnsmpoaDw+P69evr6+v6/X68fFxDw+P6Ojo8fFxevIq3o9BkAAAvERIkxHXH8/Pzy8tLX3w4EFJSUlRUVFRUVHxc4LfUlRUdP/+/Zqamu7ubj6fj2jVNOE0Rdg7giRhB4qiFhcXGxoa/Pz8Pvroo/3793t7e9fX14tEIp1Ot7W1tbW1tb29PTw8HB4efurUqa6uLoQQh8O5cuWKo6Ojp6dnfn5+QkKCi4vL9evXpVIpm82OiYmxsbFJT08vLy+/evXq2bNnCwsL8TRs6Iv10EGQAAC8RCjjgEWBQHDnzp3AwMDr169nZmbeuXMnPT399u3bGc9PZmbm7du309LSrl27dv369b6+PjKYBFLu6ewdQSKjfrRabU9PT3R09Mcff/zWW2+988477733XlJS0tLSEp6RA+eULi8vJyUlXbx4EQ/zEIvFAwMD8fHxn3zyyenTp48ePRoYGNjS0oIQkkgkJSUln3/++cGDB48ePXry5MnLly8zmUz6dkloFwQJAMBLhHQNLi4uJicnx8bGMhgMJpPZ0dHR2tra1tbW/px0dHTg9zY1NRUUFCQkJDQ0NJDJICHESmfvCJLEOQ0GA4/He/LkCYPBqKqqqqmpKSoqGhwclEql9I5omUzGYrFaW1sFAgFWmlgsHhkZYTAY5eXl5eXlg4ODEokE593w+fyOjo6Kior79+9XVlaOjY2JRCKDwWDSc45AkAAAvFTwqUOr1bLZ7JSUlMTExM7OTi6XOz09PTMzMzs7y3p+8BsnJycrKiqio6MrKipwMU58ToPTFGFPCRIZU0nxMwZjYV9kjBvgQf2IVp8Jv4q7LUmQgUTkSc8i3nXoM24jYzV9kwlAQJAAALx09Ho9l8tNS0u7devW4ODg6urq/Pz8ysrK0vPD5XIXFxdXVlZYLNbDhw+vXbtGBGnpb/nKsXcEiYzBenIFhE1mPnIIP0kKEmI1ms9+TNFm1jYYp/ugvq5KIV3AIEgAAF4cikJqtXZ2di45OfXatesjI2Orq+sLC4sLC4tc7tL8wuI3+FtcWpllc6of1sbExpeVleEqKJb+oq8ce02QdHuZ2I6+AH0Z8wFGBHrrkJRy1RvZcX8CQQIA8HL5akFy5rnP+zfHWeDMc6emWZVV1dExcRUVFSTlkATSALSXBGmuN7oFDcaJXUjhG/I8/aH5GkzGz1JfLPi048dAIEgAAF4eL70FiR05OTVTWVUdG5dQWVlJFyScpgh7R5D035WYj7yKjWXSfDTx3I6NSJz4Sm8vfpkayasIBAkAwMvjqwW58Px/8wuLC9wl1uwco7omLj4RWpBfxt4RpInD6Nk6+FVsKfoyJGcH0WRp0oIkAVV6C5I8NP8YIEgAAF4uLz3EypnncheXZ9kcRnVNdEwc9EF+GXtHkCa/LnmIm4A6nQ5XVMJP4spwxKCki9GkdWjSlKSvmTJmwJoAWawAALxcXm6IFTciuYvLMyx2FeMhEaRxW3CO+j/2jiCRWZIOvU1J2oJ0NZL0VJKAQ96O01zpT9IFSe/INMFEkN3d3USQXx2bBQAA2JFvow9ygbs0w2IzqmtiYuNxiBVvC8ZB0tlTgsRDFfGgRvqTJo1C4jbiPNzKJAuQhelSVKlU5ls0CckiM0F2dXXNzs6SMSQQ3wcA4Hl5uYLEGTq4D7L6YW1cfGJlZSU+v1FQSeeL7GVBkuk1TKoLkqAr7oOkaPmuZD06I/SuRzLvMfqSjB60UwtydnZ2x/gtAADAswCCtBR7SpAmIVZc6Qb7kiTpYIlqjODWJMlxpSgKv0riq0RseD1Yq8i4J5mMA0E79UHiCZOhBDAAAN8MCLFair0jSPMkneXl5YGBgampKalUiv0kk8lmZ2d7e3vr6+urq6txSUMyZZVKpVpfX+/u7n748GFLS8vg4CCeDxkhJBKJpqamampqqqqqGhoapqenJRLJswiyp6dnZmZGpVKBIAEA+GZAko6leFUESS5b9Hq9RqMxX4A070jbzmQBHC/FjT+lUjk/P5+ZmWljYxMbGzsxMYETc0QiUV5enpOTk729/alTp2xtbTMyMlZWVvAMotPT0/fu3XN0dHRwcDh79mxAQMCjpmadVqeQK8bHnkaEhTvYXzxx7LidjW1IUPDw4BAyNi9NqtDp9Xpc2FAgEDCZzJmZGYhaAADwjfmWWpB4HGRMbHx5eTlpQcKZis4rJEjcNUjRCqWaL4Oe4ffTarVjY2O3bt2ytrY+c+aMr6/v+Pg4fmltbe3x48fl5eVMJnNoaCgoKOivf/1rbW0tQmhmZiYhIcHHx+f27dtMJpPBYLi5ufn6XF5dXllZWo6NjnFycOxoa58cnygpKj702cFrKakrS8ukoCvZOumhRAhtbW319PSQPsiX858CAOB7BgjSUrwqgiSNwh3ViMGtTNxrSJJO6WvAr6rV6vn5+ebm5tu3b4eEhISHhw8ODuIeRKlUKhAIeDweTreprKx89913KyoqDAZDe3v7oUOHXF1dWSwWQkgsFqelpdnZ2D7p6q6uYni6e2Rl3llbWTXo9PNznMvePsGBQd2dXTKZDH8wMiwEj7bEz+AsVjabrdFoYLcDAOCbAYK0FK+KIBFC2C7T09M7prSQmOrGxoZAINhxDSQBBy88OTmZlJSUkJAwNDRE0nAQzcHl5eXvvfdefX09Qqiqqurdd98NCQnBO4pcLi8uLna86FBdxYiKiLzs7dPV0anX6hCF+Bu8e/kFgf4BxQ+KRCIRMppbJpNtbW2trq5uGGGz2Y8ePWKz2bibE8HOBwDA8wOCtBSvkCA1Gk12dnZAQMCOfZC4V0+v19+4cSMxMRGbiQ4ZjEHqwI2Pj0dHR1+5cmVoaAgnrOJlcH8kl8tNTU21trbu6enR6XRlZWX79u27cuWKRCJBCKlUqrKyMg8397KSUi8PTzfXS2MjoyqFElGIt75RVlIa4Oefk5UtFouRUd4ikai3t/fx48ctLS34tra2tqamhsViEUHCOEgAAJ4XEKSlsJgg6RVtsD/0ej2LxfLy8pqbmxsbG1tfX1er1cQoOEopEAh+97vf+fv7k5wrOsR/eHTH2NhYbGxsbGzs0NAQ3hbp4JRIJLm5uc7OztXV1bg9iluTgYGBcrkcISSXy8vLy708PCvKyt0vuXm4uQ8NDCrlCkQh0db2Q0a1r8/ljNvp2NM4nVWj0WxsbCwvL6+vr6+tra2vr09OTnZ0dOAsVpLjulv/YAAA9gggSEthMUGSjFMSUNXr9Uql0tvb+4MPPjh27NjHH3/8/vvvnzt3Ljo6uqOjAyemnj179tixY1Kp9MsyXQ20Ka7Gxsbi4uIiIyOHh4eRsV45QkgqlT58+NDX1zc5OZnL5eInS0tL33rrLS8vL6VSiTsyy8rKXJycax/WRIZHeLp7MLufaNUavU6/sbZeVlIaFBD4oPA+vQVJBlniDen1eqFQyGQy2Wz2jmV6AAAAngUQpKWwpCARQlhFEokEt9t0Ot29e/cQQgaDQaFQrK2tFRcXHz58+Be/+MUf/vCHgwcP/sd//AeHw/mK1ZL6OAihp0+fJiUlxcTEDA8P45GIOp1uZWWlvb09ICAgLCxsbGwMIYTtVVtb+/bbbzs6Om5tbel0OoVCkZqaet7W7klXd8bt9PO2dmUlpZv8TYPesMCZj42OCQoIbKxvwHsVPXMVbx2HeYVCYW9vL4fDIb2esPMBgKXYsfTVdwIQpKWwZB8kycQpKytbXV1Vq9UymayyshIbC8ddsVpSU1P/4R/+4ec//3l7eztFUeYdkMjoOUQLY87MzKSlpSUlJY2OjuLhlQqFoq6uLiEhITo6uq+vD38A3BhtaWn57LPP7O3tWSyWXq+XSCTJyWVtEogAACAASURBVMnnzpydnpyqfVjjeNHhWkoqf4OHKMSannFycIyLiZ2amCRVdch26SXO8TCPubk5ksUKIVYAsBQgSBDk82LJFiQOSHI4nF/96ld//etfk5OTZ2dnCwsLNRrN1tYWj8fr7OzMyspyc3NzcXFJTU318/OztrZms9lk9ig6xExarXZlZeXx48cRERFHjhw5dOhQQEBAS0uLRCKZnp52cnJ6/fXXDx06lJiYmJWVdevWrba2NplMxuFwYmJiHBwcwsLC0tPTk5KSnJ2db16/IRVLOOy5xPgEW2ub9Fu37+UXJMYnnD55qqykVClXGGiTWNELoOPDb3t7G9diJZ2pIEgAsBQGM74rvgRBWgpLJumQ+2w2OyMj46OPPvrZz37229/+9vPPP3d0dDx58mRwcHBTU5NUKsWLabXaq1evBgYG7rhC0v+HEBobGwsLCzty5MhhI+np6SsrKz09PSEhIR9//PHRo0c/++yzY8eOHTp06Pr16xMTE1qtdmFhITMz09ra+uTJkydOnEhKSlpeXEIU0mq0QwODfpd97c9fOHzocwf7i2mp1zjsOYP+/w4ztJMgt7a28GwepMcUdj4AsBQgSBDk82IxQZKUFoPBoFKplEqlRCKZnZ2NiIgICAhwcXEpKirCqS5k8kXcMRkZGdnV1bXjOsk8VlKpdHFxcXp6msViTU1Nzc7Orq2tqdXq7e1tLpc7Ozs7MzMzOzs7Pj4+MzOzurqqUCjwxxAIBFNTU0NDQxMTE6urqyqVCh85EomEzWaPjo4ODw9PTk7y+Xy1Wo0/GNmf6D2RMGEyAFgW84CqyQSxBuPMr2RgGP29hi9OAUuKLVsEEKSlsKQgkbG9xWAwHBwc9Hr9gwcPAgMDNzY2NBpNfn6+tbX11tZWSkrK2toaQkgsFldUVISFhUVFRe2YqoM7Gs3ruuGHZKSH+SfBuUK4yID5AibvoigKpwLhBisIEgBeQcwFSU9xp2hz9SBaJS+T95KHIMjvJxYTJGkaajSa1tbWixcvxsTE8Hi8a9euicXikJCQc+fObWxsjI+P//73v3/vvfeuXr3a3Nz8i1/8orq6Ojs7u7q62nyFZL/HNc3JwEdyhUgWICMxiOHwkyZL4tAoZcxKJdN3kBGcIEgAeDUxF6S5L+nOI2Eq+jJkVSDI7ycWHuZBzCGTyUZHR2NjY+/du1dfX//GG28sLCxgD6WkpNy5c+f111//p3/6J3d3dzz0MC0tbcfVGoyTOyJjUw+3KYnY6C0/Imk8roM+KQcyKtxk5XgBrVaLq7mCIAHg1cTciOiLU8aaP08XJ92IIMjvLZYc5oF/ErFYbG9vHxwcHBISEhgYeOzYsb/85S/79+8PDQ3NyckpKyvz9/dfW1sTi8UffvjhJ598sra2plAozIuVk/afnsaXtSPxS/SjhRwA9ElFKOMEW/SGI/1AAkECwKvJlwmSfuFLmfVBUrQIE72+Bwjy+4mF+yC1Wu3Tp089PT0DAgLCw8Nv3779m9/85pe//KWdnV10dHRMTMyvf/3rH//4x319fQihwMBAZ2fn69evf9k66cJDxikk0U6XjeQAoHfO068fiUF3jLfgZqjBOIMHeZ7c4m8nFApBkACwO5gbER+qyOhFlUqFjFWd8VvwYGvck4KtibPr8bvwfZOLbEQrCbKLXw0EaRks2YIkosK7qVwul0gkly5d+tWvfnXq1KmtrS2EUEdHxzvvvPPmm292dnYmJyezWKwLFy4ghPA8U+YrpAuSri6TLDWiQJPnEe0SknRqmguSyNVckAbaeEcQJADsGiZHK5YZsZpCodja2hKJRLiMM9YeVqNEItna2hIKhSRHD8tPo9Eolcrt7W2JRIKHMpNraPSVE/N9C18NBGkZLNmCxI5BCEml0tu3b3/00Ud5eXkFBQWDg4NBQUHR0dG4q8/Pz+/atWuffPJJXl6eRqNJS0trbm7ecZ0mgqQ/abI3U8+Ww2Z+yBELmoRbyapInJaCECsA7CImRysZfKzVasVi8djYWFNTU11d3djYmFAoxJe2CoVic3Ozr6+voaGhsbFxYmKCTD+g1+vX1tZ6enpqampaW1tnZmYUCgW9Vao3m5Lv2/xqIEjLYOFi5XgnGxgY+OCDD5qbm7VabXl5OUJILpdHR0cXFxfrdLq0tDQOhyMWi/FEx8PDw+Hh4evr6zuu88takCbNQVK4HH2JQclLOwoS0cZR7bgMPvxAkACwa5gfjAghrVa7tLSUn58fEBCQmJgYFxcXFBRUUFAgkUi0Wm13d3dcXFx0dPStW7eioqL8/Pyqq6tVKpVEIunp6bl7925ISEhUVBTuAOrv7yclo9HuVsUCQVoKiwmSBDEQQjgHB/syOztbqVSq1eqNjY0rV66w2ey4uLjZ2VmSLCOVSq9cuTI6Omq+ThNBmo/uIHfMo6MkydukZUmHHBImGW4m6T9EkJubmyBIANgdzI9WiqKkUmlLS8vly5eDg4Pb2toaGhocHBwcHBwWFxc3NjbS0tI+/vjjuLi43t7e+/fvHzt2LDo6emlpaXV1NSgoyMHBITExsaam5ubNm2fPno2IiMCp9dSu11UGQVoKiwkSd5jjH4PMB0meJwbq6+vj8/mkbxznlzY1NS0sLJiv00SQJjk4X7EkaUSaD4U0uSBFtPAseUgfQQWCBACLsOPlrEKhKCgo8Pb2Li0tlUgkMpns+vXr1tbWo6OjU1NTMTExhw4damhoQAhxOJz4+PiYmJienp6hoaEDBw6cPn16ZWUFl4a+c+fOsWPHRkZG8AkK7e6xDIK0FJZM0jGB5JuRYfh0sHKUSqWBVgKKDn4jST01GAxKpVImkymVSo1GQ+yFEFIoFFKpVCwWS6VSmUym0+nwhMYGgwHPvbW5uSmRSJRKJelo1Ol0MplMLBYLhUKxWCyTyfBoEPpHpV9X4luBQMBkMnGxcuqLUV8AAF469PQ6kg3Q0dHh6enp7+/PYrH6+/vxcLKNjY0tofD2zVuffvxJ8tWk+TlOc2OTjZV19p0s7vxCfW3d4UOfu7lewrOp63S6mpqajz/++NGjR7jGJIlR7c73AkFaildFkDisz2azNzc3v2wZvMcvLi6inXZNk0aeVqvt7e1NT0+vra3FgRGEkEqlWl1dbWlpSU1N9ff3v3r1akVFhUgkwm6WyWSDg4NJSUlXrlyJi4srLy9fXFzE3uXxeGVlZYmJiQEBAbGxsbW1tTwejzQlDV8cGYmMSTqbm5sgSADYTejnAXzGEIvFhYWFdnZ2dnZ2R44c8fPzGxwc1Ov1Oq2WNT2TcTv9gt35A598amdje9nbZ3hwSKVQVpZXnDx+IjQ4BOfS63S6+vr6gwcP1tXV4XDXLgeEQJCW4lURJEVRPT09+/btGx0dJTMe0yFhzBs3bmxvb++4EnLluL6+3tPTExwcfODAAT8/v6mpKdy4FIvFDx48uHTpkqurq7u7u4ODw5kzZx4/fqzT6aRSaWtra0pKyrlz5zw8PJydnZ2dnfPz85VKpUgkKi8vd3V19fDw8Pf3d3V1PXv2bFVVFZ6EGRnrAZE4LQmx8vn8J0+esNlskj4OOx8AfHvQEwKQ8cDc2tp6/Pixm5sbnvzO1dW1ra1NIpGoVeoFznxZSan7JbcP3//g3Jmz4VfCep4w11fXGJVV1uesQoKCRSIRjhI9evTok08+qampoQtyF78XCNIyvCqCRAh1dnb+7Gc/GxwcxLugObid9+c//zkjI2PHOZOxrnDbMTU11dPT09PTMywsbGxszGAwyGSyp0+f+vj4WFtbt7W1qVSqR48enTt3LiYmZnFxcXx83M3Nzdvbu7GxUSaTTU5OxsbGOjo6crnckZGR8PDw4ODg2dlZmUzGZDKPHj0aFhY2MzNDZnUmIR26CIVCYXd3N5vNNp/MGQCAlwtlzE4nF6wqlQof5j4+PqmpqVNTUx0dHfj6uLe3d2V5OSvzztnTZzJup8/OsOpr66zOnouNjuloay8pKj525KiXh6dIJMKrevTo0YEDB5qbm/HFLgjye8KrIki9Xq9Wq+Pi4p4+fYp2iqDixhmPx/v3f//369ev49G+5svgfVcoFM7MzFRVVUVGRkZFRQ0MDODmY3FxsYeHR0xMzMLCAkVRc3NzKSkp/v7+nZ2d9fX1+/fv9/X15fP5FEXJZLLc3Nxz5851d3enp6cHBASUl5fj1PDV1dWYmBg8VyWuV0CGJGs0GlyjFd+ur69jQZIxJCBIAPj2oL6YUo6T3oODg93d3Xt7ezUajUwmy8/Pd3FxKS8vLystjY6M8vb0YnY/QRTaWFvPy8l1dXbJz7tbU/3w0GcH7Wxs19fX8UpKS0uPHTvW2dlJr8AMIdY9jyVn88DaION5VSpVWVnZ1NQUMhZExQljZAGdTldUVPRv//Zvs7Ozz7KJycnJ5OTk+Pj4wcFBnU63tbV17dq10NDQkpKSzc1Ng8HA5/Obmpo8PDxKSkpKS0v/8pe/BAQEKJVKvV6vUCiqq6svXLjw8OHD0NDQy5cvDw0NYR2ur69XVVUFBQXl5+fjC0wsSLFYzGKxhoeHR40wmcz6+no2m00y30CQAPAtQdFqYJGjcnNz09fX9/jx421tbVKpVC6XZ2Vl2djYlJWV3Sso8PHydrC/WF9bhwzUytLyrRs37c9fKH5Q9KSr29ba5sAnn7a0tEil0r6+Pm9vbz8/v4WFBQixfq+wmCBJowrngiKEKIrKz89PS0tjs9lisRjvgjiggUOUIpHo5MmTBw4cIL75asbGxmJjY6Ojo/v7+7VarVAovHr1amhoaGVlJY7Qbm5uNjY2uri4PHjwoKio6A9/+IOvr69SqcTBmfLyck9Pz5qaGi8vLxcXFyaTiYcJr6+vl5WV+fr65ufn46lFcOeoRCJ59OgRg8Goqal5+PDhw4cPi4uLa2trZ2Zm8DoRCBIAvjV2FKREIrlx44aDg8OtW7cWFxf7+/sDAwMvXrzIZDJ7mMzQ4JCjh4/cycjkb/DaW9v8ff2CA4O6OjrnZtnhV8JsrKwTExPr6upu3brl6Oh469YtHo9HTlZoFw9nEKSlsGQlHVK/hjJW1amoqPjv//7vX/7yl//1X/918uTJa9euPX36FC+mVCqfPHnyk5/8JCcnh56oRgcvSQYdPn36NCIiIjIycmhoSK/XCwSC2NjYoKCgioqK7e1t3Hv/6NEjJyen+/fvV1RU/PGPfwwJCVGr1SqVSq1WV1RUuLm5VVdXe3h4eHt7DwwMyOVyiqJwRquvr+/du3eJILVarUKh4PP5S0tLKysry8vLq6ur09PTjx8/xkk65Fvv4v8YAL5HkMHN9DFder1+cnKyqKgoOjo6LCwsPDw8MTGxqqpqe3ubz+O3t7al37odfiUsMjwiIiw8IS6+vbVtSyBUK1V9Pb0PCu+HhIQEBASEhYXl5ubOz8+bFCjftXrlIEhL8Ur0QZLahjk5OSMjI3K5vLu7297e/rXXXvvHf/xHnCmDEDp16tT//u//4pFJO0IZ57LBv/HY2Bg+JIaGhnQ6nVAoTElJuXz5cl5eHp/PRwhtbW01NjZ6eHgUFxczGIx9+/aFhISoVCq5XK5UKsvLy11cXJqbm0NCQvz8/Lq6ulQqFUVRAoGguLg4JCTk7t27EokEGYdgGowljHF8GHeFMpnM+fl5k7GSAAB8GxBHItqxptVq+Xw+k8msqKh4+PDh6Ojo/0/xo5BcKltc4La3tpUUFddUP5ydYcmlMkQhZKC0ao2Av9ne3l5SUtLa2rq+vm6eardr9cpBkJbCwqXmSOw0IyMjMzMzIyMD151BCKlUqvn5+aKiog8//PDdd9/18vLat2/f+Pg4ThndcRykgQZFUZOTk/Hx8bGxscPDw3q9XiQSPXjwwNXVNTw8nMPhIIRYLNbNmzdDQkK6uroaGxs/+OADLy+vzc1NiqKkUumdO3fs7OzwYEovL6+ysjKJRGIwGBYWFqKioiIiIlpaWhQKBVYjvd+eJLltbW0xmUwWi0WmaIadDwC+PUgZHfIMaU2qVCqlUonLWP5fRUm9Qa/Ta9QamUSqVqp0Wp1Oq0MUovQGRCG9VqdWq9VqtUajoR/CdHbre4EgLYOF+yCx51JSUn7605+++eabEREROEkH78QIIZytam1t/YMf/CAlJQU3ztBOvyKpemMwTmU1ODgYHR0dHh7e1dWlUChwwvf58+ft7OyYTKZSqWxra7t06VJiYqJAIBgeHj516tT58+e7urrW19fn5uaCgoLs7e03Njba29vd3NwiIiK4XK5cLu/v7z9z5kxcXNzm5iZ9OmW6sw3G6a6YTObMzMxuzowDAN9niLdIU5JAYjz//wqbQnqdXqVUUQYKUUir0SIK4fs6jRbf4rWZVyff5YtdEKSlsLAgcZm38PDw1tZWHo9XWlo6MTGBjCN8ZTJZdXX1kSNHLl68mJWVtX///ra2NjwXo/lYSXx9hw06OTmZmZlpZ2f30Ucfvf/++6dPn753755AINjY2Lh58+b58+ednJx8fHycnZ29vb27u7sRQjwer6SkJDg42MrKytvb28PDw8PDo7KyUi6X8/n87Oxsa2trNze3kJAQLy8vT0/PlpYW8/mWyS1MdwUAwMsCBGkpLDnMA7cF1Wq1WCzGaavV1dVjY2N4NGFxcfH//M//fPrppzU1NXh8RXZ29ttvv72ysrLjIEiyWo1GMzU1lZ+fHx4enpCQEBUVdeXKFQaDgTfBZrOrq6vj4uLc3d3j4+Pb2tpwXR6dTicQCFpbWyMjI729vWNjY6uqqsRiMRb53NxcRkaGv7+/n59fQkJCR0eHSCQiqTcYugJBkAAAvCxAkJbCwuMgSQ0aXK20oKAgLS3t9u3bN27cyMnJGR8fx9XJceVxuVx+6dKlmzdvkpmW6WAJkd4CpVIpkUi2t7dlMplEIlGpVKQIHC5WLpPJcClzvDwOkOLCctvb29vb23hVJOlGIpGIRCKhUCgSiXAdAJO6VtCCBADg2wAEaSksKUh8hwxq1Gq1xcXFY2Nj2DoIITwekTzEkVUHBwc8HtEE4ifcqW6yLZNfXavVflmcFvsSyxs/Qwqu4uYpqZuDSxmY2BoECQDAywUEaSksnMWKRy7ilh9FUQwGY2JigqLN5kiqx5Eu99u3bz969Mh8BBJOkzG/xe08PEkNMnbdU8aJG0l+DVYj6d6naLM8khmvyKtYoiRDB1qQAAB8e4AgLcUrMQ6SUFVVNT09TR7iVDHS1sRNuunpaSsrK6FQaPJegxn4eWIyEizFsVOD2azI9I3+XyK42TLEnYhWvIO8nW5fECSwN7DU8IYXgTKWH0HG49TSn+ibA4K0FK+QIPV6fW5u7uDgIH5IHxpB7yYUCoXBwcF0j2LMBUkac2QME46R4v5IZHbY4/WAIAHAhO+iIDH0IJD5t3he8KX27n99EKSleFUEiffjhoYGXIjcQJvRjT4GH4c6CwoKKioqdlyDuSNxhyJZA+56JNeVLyhIExkjECTw3ecb6ND8CHreNbwsyObI8YvbkS8Fk5PDLn4pEKRleFUEifc8mUym0WjwzkeKmNNliR8uLS0tLi7uuAY6pNVIuhvJkkRXLy5Ik+MfBAl813lxvVlKkPTN6fV6uVy+vr4+PDzc09PT+zLo7u5++vQpj8czSQP89r8XCNIyvCqCRLS8VrzzKRQKEhghNsLPPGONYKJJ3OOI25HkyZfSB0kPrlJfTPABQQLfFUx28h2DMeaxGZPjAh9iJs0swq59EfLxdDrd0NDQ3bt3k5KSrl69mpycnPTC4OnzSktLeTwe2mna2m/te4EgLcMrJEhEaywihPLy8hBtLmLcfMQDM4ifngWSpEMZ+wtxlyR6GS1IeocEvU0JggS+Q3ytIE0ijTseGhqNRqlU4g5+8zXs2hchR65CoWAwGFFRUQUFBZ2dnW1tbR0vzPDwcHx8fHh4OK6ICbN57HksXGoO7806nQ73E+D8UoVCcevWrX379nG5XGIdiUQiFounpqZSU1MbGhqeJcRB0eaHIxe2ZD4sk9ArWYCcAgzGISj4If6EJnY0b0ESE1MUtbW11dvby2azyWgQ2PmAVxCDwYBHDxu+suvBYKxyTA4WfEDhMVo6nU6tVuOxUjteWe4CdEHK5Yrs7Fw3N4/6+sbNTeHS0go2Cvl7FpHMcRc589z5hcU5zsLy8ura2kZiQpL9+Yu9zD61TEWZVS//1r4XCNIyWHg+SPozePi/UqlkMBg/+MEPTpw4odPpcChDpVI1NDRYWVm99tpr//Iv//L222/jXJ6v3QRFG86IaE1P6ovZpxQtI9xgDOHih2RwJMmqJatFX1IznS7Ivr6+ubm5XQvFAMA3AF+bkktAclDQ2390O+J6yAZapz5Znty3uCClUll2dq6Pj29T0yMeb3N5eZXLXaL/LTzDH2dxaX5hkbu4PL+wuLq6vr7Oi4tNsD5n09XRrZIqkWHni4lv4XuBIC2DxQSJ22SkoUaioPfu3XvttdfOnTvHZrNbW1utrKxItg4Ojba2tv7mN7/p7e392k3gXZYcMLg+nFQqXV1dZbFYbDabw+EsLy8rFAqDsadTIBDMzs5OT09PTU1xuVxcAxYPnVxbW5ucnBwfH5+dnd3Y2MBTX5lEYpGZIJlM5uzsrEVSwwHgGdHRIPszfd9GxtqQ2Iv4Pv1ak8ylQ31J98TufBH61iUSaW7uXX//wKamR0tLK3Nz8/PzXPof5xn+2AvcOc4CZ57LnptfWlrZ2OBfTUy+YGff86RXJVUiPQhyj2P5ECv5PVQqVVFR0RtvvNHc3IwXKC4u/tWvfnXnzh2pVEquWKenp3/zm9+MjY197SbM91q1Wt3a2pqYmOjo6Hju3DkHB4eIiIjJyUmEkFarXVtbu3//vr29/ZkzZ86cORMUFNTf34/PBSwWKyIiwsbG5vjx4ydPnkxMTMQDMfXGonQmvZJEkN3d3TMzM+TDw84HvILQ+xfonY70FiF+hvQv0p8nRa/ICl+FFqRYLMnOzvX3D3z0qGV9nbe0tPLiLcjV1XUcYu150isXyXQq3e58TRCkpbBwiBXHM+vr6/v7+xMTE/39/dlsNm5Z4pmwqqqq3njjjZ6eHtJcm5yc/OUvfzkwMPAsm6DvtWq1en5+PiIiws7OLikpqby8PCYm5vjx4w8ePJDL5SsrK9nZ2aGhoaGhofn5+fHx8Q4ODklJSRsbG6urqzdu3HBxcbl27Vp+fn5ERMSJEyeys7O3trbMTyVfJkjY7YBXFuI2esuPvm8TcdL1SZxK4q70dqTFBSmRSLOycnCIdX2dt7i4/OJ9kBsb/MSEq7bWdl0d3XKRjNLsUkMZBGkpLNyC1Gg0c3Nzv/jFL377298+ffoUJ6niW4qiFAqFWq2uqKhwdXUljbDh4eE33nijo6PjGTdEN3F7e/u5c+dOnz6N/drd3X3hwoXExEQejzc4OHjmzBlXV9eZmRm9Xr+9vZ2ammprazs5OdnU1OTu7p6SkrK+vo4QmpiY8PDw8PHxGRgYwOFZhJBKpTJpQRoMhq2trZ6enrm5uV3LdgOAbwDWG6JNKWwwGKampvr7+9vb2/v6+hYXF8kCWq2WzWZ3dnaur6/jrDq8w4vF4qGhob6+vtbW1r6+Ptx5gYyjtnYHfGGNj0GZTJ6ff8/X17+mpo7H2yRG+WaC5MxzsSDjYuOJINFupRaAIC2FJVuQCCGFQsFkMl9//fWf/OQn+/fvFwqFZK5H4h61Wu3l5cVms/Fx2Nvb+9prr42MjDz7hrCuxGLx+Pi4ra3tgQMHmEwmQqijo+Po0aN37twRCASPHj367LPPPD09NzY2EEJSqTQ7O9vOzq6zszMvL8/Ly6usrAzPHMnhcGJjYwMDA1tbW2UyGWUcBGagZcPi2+3tbSaTubCwQM8Geun/SQB4QSiKInPXIIS0Wi2Lxbp69aqjo6OdnZ2rq2t9fT2fz8dZPHw+Pzc318XFpby8fHt7mzSeRkdHo6KiLl26dOHCBU9Pz7y8vPn5ebSLgwWRmSDv3i3w9fWvq2vASTogSBDk82LJ6a4oY/f+5uZmfX29jY3NG2+8cePGDYVCodFocnNzjx8/jic9PnHixOHDh69cuRIbG7t///6PPvpoeXn5GTdEBKnX64VCYU5OjpubW0REREpKytWrV6OjowcHB1UqFYPBeOutt/z8/JRKpV6vV6lU5eXlzs7OVVVVISEh3t7evb29KpWKoigej1dUVBQUFHTv3j2JREK+i1QqnZycHBkZGRkZGRwcHB0d7ezsxMXz6CMvv8X/KQB8IyiKomduT0xMxMbGhoeHp6SkZGZm5ubmDgwMqNVqhULR29tbUFBgb2//7rvv3rhxY21tDQ9/nJ+fv3PnjpeXV0JCQmFhYXBw8NGjR+vr69EX8wy+bejhX6lUlpt719fXv7GxeWODz+UugSBBkM+LJae7MpgNH3769On777/v5OTE5XKDg4M/+OCDY8eOOTs7Ozk5Xbx48cyZM9bW1v7+/uaVyr8CIkiEkFwu7+vrS0pK+vzzz3//+9+fPHkyJydnbW3NYDAUFha++eabwcHBuJq5RqOpqqry8fGpqqry8PBwc3Pr6+vDcdTt7W0Gg+Hn55eZmSkWi5ExrLq9vd3d3d3S0tLS0tLc3NzW1lZdXV1dXT0zM6PRaOi11wHglYKiKBIIxclxx44dq6qqEggEWJz4aBWJRDU1NXl5eVFRUUePHs3KylpbW1OpVGq1uru7OyAgIDU1lcViURTV2tr6zjvvpKenI2Miz659EQIe5nH5sl9z8+O1tY35eS4IEgT5vFiykg5WF567mAw3Xl9fj4iIOHbsGJPJJDkC3d3dQ0NDOp1OLBYbDIbn6tUggtRoNNvb2/n5+e7u7qGhoZGRkW5ublZWVg0NDVKptKKi4t133w0ODsZzIKvV6srKSk9PTwaDcfnyZRcXl/7+frwPCYXCq4SfjgAAIABJREFU0tLSgICA3NxcPNiDpOfI5XKRSCSRSEQikVQqXV5e7ujomJ+fh0o6wKsMFiQ2mUAguH79+rlz57q7u7e2tlZXVwUCAZkDRywWCwSChoYGW1vb69evb25u4lyB3t7eqKiooKCgzs7O5eXlqqqqw4cPl5WV7WaSjslWZDJ5dnaut/fl5ubHKytrHM4CCBIE+bxYTJBYcvjHUKvVpAMPt7R4PJ67u/vW1hZCSKvVrq6uHjx4kJ6YQ37Or4UIUqlUtrW1RUZGBgcHt7a2bm5uNjc3X7lyJS4ubnBw8OHDh/v27bt8+TLu+1QoFBUVFfb29g0NDfHx8e7u7h0dHVKplKKotbW1e/fuBQcH5+TkyGQyeg08fKIhw8IEAgEk6QCvPmS/VSqVc3Nz0dHRBw4c8PHxCQoK8vX1vXPnztzcHF4StwXb2tqcnZ1zcnL4fD6++JNIJM3NzXZ2dv7+/sHBwaGhobm5uRsbG6T+xu58C/pDXEnHy8sHj4OEFiQI8htgyT5I7Egcn9RqtVwuVywWY9NotdrBwcGMjAxS2nF1dfXixYs3b94UiUTPO+4eX8Py+fysrKyLFy9GRkYuLi7q9Xoul5uWlubi4tLV1dXa2vrhhx+6ublxOBy1Wi0SidLS0mxsbKampkpKSlxcXPLy8kQikV6vn52d9fT0DAsLGxgYwL2SZBOIVjzWYDAIhUIoFAC8+uD4CtbkxMREUFDQkSNHEhISMjIywsLCXF1d09PT8W6ML2Tb29vPnz+fnZ3N4/FIHY++vr5z586dOnXq4MGDR44cuXv37urqKqKNIdllpFJZdk6et49vfUPTyur6HGfhG4jERJA83iYZ5qEQy9FudZuAIC2FhbNYcTATIdTe3v7WW2+dPn1apVIhhHJycmpqanAhGz6fj2dwnJyc/PWvf+3s7Py816TYXhKJpLi42MXFxcfH5/HjxzMzM42NjZcvX46MjJyammKxWD4+Pi4uLnfu3Onr63v48GFwcHBkZKRQKBwZGQkJCXF3d29ra5ucnCwvLz98+PCtW7dwV6VJeioIEvjOQcpcqFSq8fHx0NBQKyur4eFhrVY7PT0dHR3t4ODQ2tqKD1WE0JMnT+zs7DIzMzc2NnDWKK7y4e3tffXq1bS0NHt7+wsXLrS3t5PZ63b/S4EgQZAvjiUFSXI7Ozo63n33XW9v77KyMqVSyWKxTp069frrr7/99ttvv/32n//857fffvv9999/8803f//73//pT3/q7u4mx+ozbgvD5XIzMjIuXLhw/vx5Ly8vJycnNze3trY2pVIplUp7enquXbtmZWV18eLF8+fPx8bGjoyMqFQqlUrV1NTk4uJiZWV19uxZZ2fnmJiY0dFRZBwxRt+lQJDAdw58MOLBHjjEevHiRQ6Ho9freTxecXGxvb19bW2tVCrFCd6tra22trY5OTk4iCqTySorK11cXMrKypaXlyUSyePHj62srG7evLmwsGCpDDUQJAjyxbFkFisZfdXe3s7lcvW0+Y2bmpqYTKZMJuPxeBRFqVQqDoej0WhmZ2fX1taet0uPCFKr1a6srHR1ddXV1VVUVDQ2NnZ1deHDXq/Xq9VqDofT3NxcU1PDYDBmZ2cVCgV228bGRl9fX11dXWFh4aNHjxYWFuRyOV4nfUIPBIIEvpvgIA1CaGtrKy4u7uDBg7iYBofDSU1NdXNza25uxn3wCKHe3l5nZ+e7d+9KpVKEEI/HS0tLO378eHNzM05bGx8ft7KyCgsLGxsbwzGh3QcECYJ8cSxcSQcnr5oID1dM7evrw7+ZRCLB7UVsnW9wNUo6CHEcCV/SSiQSHBpCtHmPcWFJtVqNR3SQsjg4moqMFXNwvwu9JgDZFggS+M5B0aYQ12g0d+/exSUY5+bmGAyGj49PcnIyntZUIBAsLCwUFhYePXr0ypUrzc3Ny8vLMpmsoqLCwcEhIyNjaGhodXW1rq7O2to6MzNzcXHRUhlqIEgQ5ItjyWEearWangKOU1hxs7K1tbW9vR0ZpyQl9R4RbdrFZ9wKfRwksSBlLJdKry1JqjjiW1KCmfpipWb8Cel1KendkCBI4DsH/QJRr9ePjIyEhoba2NjY29s7ODh4e3t3d3fjggD19fWRkZEnT57805/+9Omnn549ezY/Px8PoEpPT7e1tb1w4YKbm5uTk1NgYGBfXx8+iCDE+oKAIC2FhcdBkh+D3MHHklgsxpNMkSwYekj2ebeCNfZlH8B8qBZ+SLS647tMnEpeJSamYLor4DsC1hg5UuRy+djYWEVFRUlJSW1tbW9vr0gkwoux2eyOjo66urq6urr6+vqampqBgQG8z3M4nIaGhoqKCgaD0dzcPDExIZFI8DFrkflQQZAgyBfHkvNBmkQm8TAsLB5EKyOAaPFYhJBAIEDP8yuSw556NuhtSnr4lH4HBAnsJXC6HNn/sdXURpDxICIpqbgnAu//+AglBwV+C31+Dxjm8eKAIC2FJQVp8gwJVKpUKhznWV5eJh0YJG01JycHPfMUAXTtfWNBUrQIKvpi+xIECewB6Ds/ERtlDLrSry/x8vTed3IgY61iNRKDkud3/0uBIEGQL46Fx0Fi9Hr90tJSSUkJjqnq9fq1tbW//e1va2tr+GfDB5hWqxWJRP/93//d1NT0LL/ijuYzERsd9EX50Tsdv0yxIEhgD0C3o8mhgRegB2AQbe4aZDyQyXvp69HT5obc/S8FggRBvjiW7IPEUBSl1Wrd3NxOnjyp1+tnZmZEIpFIJAoMDJyamuro6MD1HnH0tbS09F//9V/r6uqeJW7zDQRp8l4QJPB9wCQWQg4uen8HfoYcCOiLZ1LyRpzgTQ4Wknm3y98IgSBBkC8DC7cgyZG5urqakJAgFAqPHDmysrKi0+mam5sbGhr+8Ic/1NXV4R4RPp//t7/9zc7OjhT++NpN0MVmMM4VZ6DlryJaUiu+Q+JLarWaJC/gO6TfhSxv3klJ0RJlBQLBkydPcH68AYqVA68q9CSar712xEshpKP/GSiN3qDWG9Q6vUqnVxkM/6cOihaG3U1AkCDIF8fCLUh686uiooKiqOvXr4+NjSGE6urqFhYW8vPz//M//xOPVszOzv7nf/5nJpOJx4d87crNW34mYxZVRvCrJLmAPCQHNkk6UKvVuC2LnwdBAnsAeqNwx2CJ2TsohAz0P61WrdNp9HqtwaCjKL3B8IVQLQjyBQFBWgoLJ+mQI1CtVpeWliKEGhsbcY3jhoaGzc1NPAb51q1bra2t+/fvb2pqwtNRPcsmTI520nzEkMw90nakJ/JhHZIWJGVMWyXnEXryAtkcAkEC30FMdGjeGWH+DhNBGgw6+p9Op6Vfa1pktwdBgiBfHEu2IEkPB0JIp9NVVlYihBobG/l8vkKh6OrqYrPZBoNBIpEEBAT87ne/q6qqQsYBkc8ysspEkAaDAVftIXuASajWpDcRGcNNZFv0xAS6CMmTCAQJfAehe5HaCfN3mAgS/+EBIHq9VqfT0tcGLcgXBARpKSzZB0l673GL8MGDBwihmpqapaUlhFBDQ8Pq6qpKpRoYGNi3b9/NmzfVajWXy3322ZJNBEmagDqdbnt7G1dVFgqFeOu4IoFKpRKJRDwej8fjKRQKMsZLq9VibYtEos3NTVz9DpevBEECewB6Y/EZBGmKeRuU/hII8gUBQVoKSwoS9yxqtdq0tLSKioqQkJCqqqqEhIRbt25VV1dHRUUlJiZGRkbGx8fPzMwghAQCgZub2/LyMimv87WbMDnIserm5+fv378fHBzs7e0dGBjY1dWlVCqxz7q7u6OiohwdHb29vbOzs+fm5rBQuVxuYWGhn5+fk5OTv79/cXHx2toa3b6IVtOOuJ/P5z958mRmZoae1/ct/18B4LmhaElnOiM43IJ3Xc2zodVq8VtInz2p14hoV5C7cxSAIEGQL46F+yA1Gs3o6OhPf/rTv/u7v/vhD3/4wx/+8Ac/+MHPf/7zH/3oR3//93//4x//GE8pgIyFAmpqam7duoUQIj/ns4Nr1w0PD2dmZsbGxiYkJNy4cePatWu9vb0ymUwsFldUVERFRfn4+KSmpkZFRV28eDErK0sqlW5vb5eWlnp7e8fExCQnJ4eFhZ06daqsrAwP2aTMRkwTtre3u7q6pqen8WkCwc4HvJKQXVepVK6trc3Ozk5PT4+Pj4+NjY2Pj7NYrImvY9KM6enpqamp8fFxLpeLj1YQ5DcGBGkpLCZIUmuDoiipVGowGAoLCxFCjx49mp6exg+PHj363nvvNTQ0YDuq1WqJRGJlZdXX1/cNtkhRlFAojIuLO3HixL1793AVArlcrlAoDAbD4OCgs7Ozi4tLa2urRCJZWFgIDAy0sbGZmpp68uSJh4dHeHg4l8vVarUjIyMnT54MDw+fnJwkRz6BrkxcrHxubg5CrMCrDGWcAIDFYpWXl2dnZ9+/f//+/fs5OTl5eXkPHjwoNOV+YeED+l9BQSH9r7Dwfn5+/v3799PT0wsKChYWFvCkcggE+Y0AQVoKCw/z0Ol0crkc36+urkYINTU1yWQyg8HAZDIXFhZCQ0N/9KMfpaWlZWVllZSUFBUVHT58+MMPPyQty2eHoqjp6WlPT09ra2s8VkQoFCoUCplMhhBqbGz885//7OrqKhAI9Hq9TCbLzMy0tbXt6upKT093c3Orra3FLy0sLCQnJ4eEhDAYDPxeer+jSqXCs2VpNBqBQNDW1sZms58xJgwAloKiKLFY3Nzc/P/Ye6+guJIsffz997gbsbuxG/syEfuyEzuxszO7s909//Ez3a2ZnVZ3Sy3UUssg4UHCG2GFHBIgixFOQsJJwlN4kIR3hbdVBeW9oyh/y9yb/4fsyk6qSoAAASPdLzKIourem+Zm5pfn5Mlzrl27lp6eXlRUVFFRUVJSUlJSUlpa+tgdpY8fP8HTo0el69Pj4uLi0tLSlJSUyMhIaJoOrQf2bCDQBEkT5M6xnxIkiUWSIkmytraWoihom+NwONra2kQikcViyc/P/5d/+Zf//M///Oyzzz7++ONPPvnkZz/7WVVV1dvmSBDE69evQ0JCTpw4kZmZeefOnRs3bsDdRABAdXX1J598EhsbCznPZrNVVFSEhYU1NzcnJSVFREQMDg5aLBaHw6FSqZ4/fx4bG1tZWQkDxsIqaLXasbGxnp6enp6e169f9/b2trW11dfXz83N0Z2PxkEGHIlarZbBYNy/f7+ysnJ4eHhmZobJZE5OTjKZzHE3MCfGmVMbJCZzYnx8fHJysri4OD4+/tmzZ0tLS7iidQ9AEyRNkDvHfkqQpCtQHPwLOa+9vX1ychIA0N3dzeVy4ZWJiYkBAQHQptRgMGg0mm1kp9Pp6uvrAwICjh49mpaWVlRUdPny5eDg4OrqaolE8uzZs9/97ndXr16F6lyr1cpgMMLDwysrKy9cuBAcHDwzMwMLoNVqGxoaoqOj8/PztVotcHUpnU63tLTEdGF8fHxgYKCpqYnD4aCDm/sS94cGjY0B9f86nY7BYDx69Ki3t1coFEokEh6PJ5FI4Od1EMskYgWexCI5nkRCiUwmk8lk9fX1ly9ffvLkydTUFNQV0QS5DdAEuV/Yf1+sEBRFPXv2jKKozs7O8fFxh8PR3t4uFAqhLZxEIvnqq696enqAK47HNpjGaDTW1dWdOXPmzJkz3d3dBoNhdHQ0NjY2MjKyr6+vrKzso48+unLlChzGBEE8e/YsODi4trY2Ojr64sWLo6OjyDa1trY2KirqyZMner0euOYX6HzAYrHYbDaCIGw2m0KhGBgYwFWsdOejcQCBVngMBqOoqKijoxNOoFyeYIu8ssLlQyLh8gQ8vpDHF/D5fLFYXFtbm5iYWFlZOTk5abVa9/K8B02QNEHuHAeFIB0OR3FxsdVqNZvNUG/Z3t4uFoudTic8DcJmsxMTE4FL3NzGW3Q6nR0dHREREQkJCSwWCwAgl8ufP38eGRnZ3d1dXV39s5/9LDY21mw2AwBsNltVVVVgYGBXV1dmZmZoaGhPTw8smEwme/To0dWrV9va2iCb4gY4uDMBnU5HEySNgw+aIGmCpAnSKw4KQQIAFhYW4HEIKB3W1tYymUxkXwcAKCoq4nK5FEVt44wHAMBgMDCZzHPnzn3zzTejo6MkSbJYrDt37iQkJAwPD7969erzzz8PCgricDhOp1OhUGRmZp49e3Z8fPzFixehoaFFRUUKhYKiqIWFhfDw8JSUlLGxMaiPRRIkLCo6H6nVammCpHHwsfsEyePzeDyRSFRTU3Pp0qWKigqaIHcCmiD3CweIICFg1HIAwOLiolwuBwDAo8cAgKWlJRToansjTa1Wx8fH//73v7958ya0R/j222/z8vLkcrlAIEhKSvLz80tPT6+srMzJyfH19c3OzjYYDBwOJy0t7dSpU8+ePYN3ffnllyUlJfA0NKAJksbfON4dQVZXV9MEuXPQBLlfOCgECQ12kDdURJPA5XwVAGAymdhs9rbfH0VRer3+8ePHp06dOnXqVEhIyJkzZ44fP97e3m4ymWQyWW1tbVxc3BdffHHmzBkfH5+AgICmpiabzaZSqYqLi//yl78EBwcHBQX5+fn5+vp2d3cjvzmIICmKgiWHdrnQ1RxNkDQOON4FQXK5XKFQWF1dnZCQUF5eThPkTkAT5H5hnz3pAEz8gvY4yMIFBd+A/gSQMxqBQLDFaB4Q6GAy5GClUjk2NlZTU1NeXt7Q0PDy5UuNRkNRFEEQWq12YmLi2bNnz549q6qqGhoa0uv10G+cSCRqbW2trKwsKytrbGwcGRlZW1vDo3+gXJBXHegoYGhoaHl5GXE83fneMyAHEW/6CX32dIW/wfV7DJj16uoqTpB8gQjOpFsikhUefuUKl+dJkBaLhSbI7YEmyP3CPkuQeKAMi8Vit9ubmppguCvINPDoIQAAkWVpaWleXh48rbgpKFdcKgoLUGW3281ms16v1+v1nkf4ob9yzzNbVqtVKpUqlUq9Xo8THvLyjGgYedJRq9XDw8MrKyuwCoDufO8pUDeA/kg3pQHKFb4bdqR97xWIIJubmyFBcnkCvkDE4wuRKLlFgoSi5MoKlybIXQRNkPuF/XQUAFzWN06nE0bGkMvlX3/9NXRN7nA4zGYzjI2MBDWSJM+dO/ejH/2Iz+dvmgWFuWBGhqZQTkWsCecpFOUD+WuGxYOfccNU9HCkE3a6gCtaEUEiCdLzCTTeA2wqFLpFyXAL/4I6Nup4e1Fob+WkCZImSFde9Bz1A/Z/DxKtoOEbevHihVqtpihKoVC0tLQAAKDeFSpdAQA///nPY2Nj4dmPTZ+MExgiQnQBZLUtDto3heNwU7K5ESTcg6QJ8v0GhQVyQUsu/CekXXC7nsSijYL96x40QdIESROkV+yzqzk4O2g0moSEhE8++aSvr+/ly5dzc3MAgKSkpH/4h39IT08XiUSUK2xkTU3Nf/zHf0Bv5ptm4bZCRzSGEye6mMSCu0K7WShTIgkSCQE4wPoZEHgQZH9/P5vNRjEs6c73ngH1K6gFgcs41DFQH4ORZFA/RPei/XU8LNTegyZImiBpgvSKfSNIFKYYANDa2vr//t//u379OkEQTU1NKpWKJMnm5uZLly799Kc//fd///dXr16ZTCaNRvP73//+/Pnz4O3fIqI3nMzc1KdopkMHSyjXziX+KJwdkRCAZjc3guzr66MJ8v0GRVF6vX55eXloaGhmZobD4aytrcGfnE6nXq/ncrn9/f19fX0CgQD1Q5PJJBAIZmdnmUzm6OjozMyMVCrdejDwXa8CTZA0QbryoueoH7CfVqxw1azT6eLi4p4/f24wGOx2e1dXF4wPNTo62traKhKJbty48emnn966dSsjI+MnP/nJ+Pg4cDHrxsAFRDdFFi5Zoi1JaGHhtvzHRUNcSYue4JYphdmyQhUri8Wiw129r6Aoam1trbe3Nzc3NykpKSUp+dqVq/29fUa9welwWkzm4cGhB/fuX02/cik+ofBhwcLCAnQ3IZFI7t27l5SUdP369bS0tFu3bo2NjVmtVihTuulp96AWOEG2v/0xDw+C5HG5fKFQXF1dm5CQWF5eOTk5bbUSeykh0wRJE+TOsZ8qVuRVtb+/H5KN1Wrt6OiABzmmpqY6OzuhoDk6Ovqv//qv//iP/9jc3AwAWF1d3UoWSFhETIbzIjLMQQpV/F648elmUoFMewBNkDQAAABQFMXhcG7cuHHz5s0nT57cyrjp882x6Mio6ckpjUo9OjySlpIafuFiR1t7Y33DxbALwcHB3d3dFEVNTEx89dVXR44cyc/PLy4urqysRIG1qfW2Y3tTC5ogaYJ05UXPUT9gn410oC9T6OMUvpj29naZTAYAYDKZ9fX1cBE9Ozv7b//2b3/3d3/X3t4OzXO2IkG+ab8QSo1QWMTjNuM3opOX6F6A7VPiMqhnpoAmyA8GNptNIpFUV1d3d3ez2eyujs5L8QmB/gEtjGapWFJUUHjm1OmM6zfYSyw+lxcdGfXpp5+Wl5fbbLbx8fFDhw7FxcVNT08vLS0tLi5qNBrUnVAv3RudJE2QNEHSBOkV+7kHifhGqVSikxLt7e0ikchqtQ4PD79+/VqlUj179szf37+srKyuru7HP/7x+Pi42WzeupEOTnI4QUKpEdm4UpghIn4v/iV6Am6y6JkpoAnygwFFUTabTa/Xm81mu93O5/IqyspjoqIfFZeIhaLoyKjoyCgOi20xmQEFnpY+OXz48J07d9Rq9czMzOeff37lyhWFQmEymcxms6d1j5sd2TutBU2QNEG68qLnqB+wbwQJx6TNZjOZTGfOnLly5crS0pLNZuvt7WWz2Tqdbn5+PicnJyoqKjs7WywWAwAIgigtLb148SLY8lvET6G5ZU1hBjs4j7qJkm6Wh8C1uqcJkgZwqeJRL1rhLN/Oyk5OTGphNPO5vKiIyMjwCN4Kl3KSgAK11TXHjx9PT08XCoULCwvffPPNmTNnnj9/3tPTw+VyLRYLOn2L61r3oBY0QdIESROkV+wbQaL1skgk8vHx+fjjj3/xi1/8z//8z8cffxwaGnr79u2srKzo6OilpSVktgA/JCQkTExMbDEXN7kQD5UFtazARWa4ZwCr1YrLlGjCgpb6pMtFgJsCFqdG/JgHTZDvMfAjQCaTqbuzy/fM2SuX02USqVatqSgrDw0OSU5Mqigrr6upjbgY/umnnyYnJ/N4PD6fn5GRkZCQcOfOncuXL8fFxTU3N6+trVHYBiSuuninoAmSJkiaIL1iP/cgCYJArrY0Go1Op5ucnLxx44a/v/8XX3zxz//8z3//938fGhq6vLwM2Qu+uVevXiUlJW09F8RzAAB44AzGqJJIJCMjI8vLy0ajEc1EarV6cnLy5cuXfX19S0tLFosFFs9kMs3Pz7969aqtre3ly5fwLkSiKBfgLZoHJEi6272XgA644cJrZGQkJSk5KCDwxbPnVrPFRtiW2ZysW5lnTp1OupSY+yDnq8Nf/uEPf7h27ZpAICAIYmZmZmhoiMlkFhcXf/755xEREdPT0+jI0J7pVwFNkDRB0gT5Buyzqznk40YoFEK3q21tbWw2myAILpfb3t4eHR39u9/9Ljw8vL+/H27VaLXa5OTkoaGhLWaECBJ3uyoSifLy8o4fP56WlraysgLFUy6XW1NTExgYeObMmVOnTl26dGl4eNjhcBAEMT09fePGjcDAQF9fX19f3+vXr09OToL1rslxCRJCq9UODQ2x2ew9s7agsceAr9VisSwuLmZmZibExdfV1GrVGspJkk6SdDgVMjl7iTXBHOew2Pm5eYcPH87NzYVmaARBwPDgMpnsypUrISEhzc3NyNWAm7b/nYImSJogaYL0iv2UIJ1Op9lsBgCoVKpjx451d3cTBPHy5UsUBhKOW4PBcP369R//+Me3b98GADgcju7u7oKCgi3mgmtZIUeazebGxsbo6Og//vGP33333fz8vMPh4HK5mZmZly5dunv37sjISEVFRWRkZGJiolqtFggEd+7cCQkJaWlpYTKZJSUlR48effDggUqlwnW2lMvdD+U6EAKjedAE+R4DvvTFxcXExMSUlJTe1z1qpQpQAFCAIimHzU46SUBSlJOknGReTu5XX31VVVVltVqRVh8AYDAYMjIyAgICGAwGPFy097WgCZImSFdeNEH+gP3cgwSuBfjExMTnn3/+85///Isvvrh48eLY2Bjcg0H+3giCmJycjI2NvXDhgkwmU6lUo6OjW8wIESSKNykSiVJTU/38/EJDQ0+ePDk5OUmSZF9f3+HDh8PCwiYmJiiKkslkt27d+vbbbycnJ+vq6iIjI+/evSuRSCiKWlxcDAoKSkhIGB0dhb0KKVfJ9R7MNRpNT0/P0tISbqD4rhqUxn7A6XRyudyrV69+9NFHAQEBDXX1LYzm9tY25hjTZDDyubyB/gHm6NhAX39JUXFsdEx2djaTydTr9dPT062trS9fvhweHq6oqDhz5kxaWtr8/LybJ4q9qQVNkDRB0gTpFftGkARBQMUmCg/E5XKzsrL+6Z/+KTw83GQyISeWwHUA0eFwFBUVRUVFgbd5i257kCsrK83NzXFxcQ8fPszPzw8MDISueRgMxn//93/HxMTArGFcrXPnznV0dFy7di0xMbGtrQ1Kh0qlsqCgIDY2trKyEjoVg/Ki1WpVKBRisVgul8tkMrlcvrCw0NXVtbCwgARNWo58z0BR1NjYmI+Pz7Fjx2JiYlKSkpMTk9LTLhcVFOq0q+NjzEfFJRnXb9y8kRHoH5CdmSUUCgmCUCgUjY2N169fT09Pz8jISExMDA0NffnyJVSoAI+4H3tQC5ogaYJ05UUT5A/Y/2geEJBjCIJ49eoVclmJA/q7cTqdDQ0NTU1N0NBmU1DYsUWn02kwGEpKSsLDw8vLy5lMZl5e3vnz56emppxO5/Pnzz/4bmuNAAAgAElEQVT++OP4+Hiz2QyDNtfW1oaFhdXV1V26dCkkJGRgYECv1wMAlEplbW1tdHR0cXExjKgMc4Eux1pcaG9vb2xsbGlpgVuqqDy722409hckScrl8qamptra2tbWVgaD0dra2tTUND4+bjKZdDrd0NBQVVVVWVlZb2+vSCSCGlQYuLu/v7+qqqqioqKxsXF+fh66KqU8sAe1oAmSJkiaIL3ioBCk2Wx2YvHwoIcdNyCa6ejo2HrAZESQBEHw+fzY2NigoKCFhQW9Xn/nzp3z58/Pzs46nc4XL1788pe/jI6Ohqt4i8XS0NAQEhJSUVEREhJy4cKFmZkZKNRCgoyIiMjLy0MECfXAKpVKKBSKxWKxWCyRSNhsNnQtSzsrf18BV3IEQVgsFqPRaDAY9Hr92toajGNKEITRaFQoFEql0m1JR5Ik9L+vVCqhHTXw5qqJJshtgyZImiB3joNCkGgusNvtXtkRAAAFOPh3i28RJ0i9Xt/c3Ozr6xsWFjY4OMhkMhMTE0+ePNnV1WU0Guvr66GKFRpQWK3W2tpaPz+/6urq8PDw8PDwubk5yN9KpbK6ujo6OrqwsFCv18NJDXk5x61YdTpdT0/PysoKvQf5voJ0+dxHkdHQlgF+0BY/HUth52uRr3x0DU2QuwWaIGmC3DkOCkHCmQUA4HA4TCaT50uCCiiTyQR3+7b4WJwgNRpNWlraiRMnIiIibty4kZSU9PXXX//mN7+5desWm82uq6v71a9+lZiYaDabCYKwWq0VFRV+fn4vX75MT08PDAx89eoVLINcLi8oKEhOTq6vrzeZTJD8YOHRJAhzVKlUg4ODHA6HdhTwvgL63MeZDH3GTbcozO7G82IKCx1DE+RugSZImiB3joNCkEgBtYGNu8PhQFYMWwROkBaLpampqaSkpKysrKKi4sGDBydPnvzjH/9YWFgolUp7e3s//fRTX19feCxSqVTeunXL399/fn6+trb2woULBQUF8FzH0tJSeHh4SkrK8PAwQRDIpyvKjqIo+KVSqRwaGmKxWMhz2E6aiMYBBE51uBbBzTUENPuC8dSQlxwS81lIuUIu0wS5W6AJkibIneOgECQkFfDm14NIaOPLPO9CBGm1WtfW1kQiEdwmHB0dvXTp0uHDh7u7u+12O5vNvnLlyunTp69cufL8+fOcnJyQkJCsrCyDwbCyspKWlnb27NlHjx7V1NTcu3fvu+++Kyoq0ul0bo7OgWuuQa7mBgcHoY/ZvTRKpLFnILH42Ghh5NYrcHjlP8SUyIUhjj2oBU2QNEHSBOkVB4Ug3xHwSQpOXpCr7Ha7TCarqKhISUmZnZ0FABiNRiaTeefOne++++7cuXN+fn6pqalzc3NWq9VoNLa1tV28ePHcuXPnzp3z9fW9du0avMvrZOdGkCwWa19Of9PYA7h1AJL0EjqGdLkd96pEhc/BBUqaIHcFNEHSBLlzfEAECTVgaNKx2WwKhWJ5eRlZ/ZhMJrFYPDk5OTg4ODo6yufzYYR3uPe5tLTU19c3NDQ0Pj7O5/OhTnhTgoS+WJHhBo33DG4dAI9yTGK+KRB9euU/yuWgHPYTmiB3BTRB0gS5c3xwBIlCc3heCYU8kiRhNA/0E+nyRg0dlAPXeh9smSDxiXLP6k5jD+CVIFEfcHMx+CaCBOsDq3kVMfegFjRB0gQJaIJcjw+IIPGFPOUypsA9eyHyQxE54GSHrPBJLMYC5TLK2Jgg+/v7kS9WmiA3wKbEsC/MsSncikRi4bg941V5VsGtOvtVKZogaYKkCdIrPiCCBB4mshRFEQThtmwnXdH4EBdCy0MAALRZBZhMuXWCPFDT+gHE+0GQwHVgCe06uxGk5xP2OPSjV9AESRMkTZBe8T4TJFqVw3U9DHeM/0RiB9RILEot/gQ37kTCKLzA7V/0ZK8qVkB3Phe8Sk5wEw5vQCiKURQFY2XDYxL7TicAAIoCMH+z2aLRaFZXVzWaVaVSpV1dRUmt0SpVGrVmXfKEVruqUmnkcqVWq9VqV7VarU6ng2Em92wdQBMkTZA0QXrF+0yQwKU4xaU6gJ1WpAlyv+AmBaJFDHReT7m8uqMGdzgccH1Duixf9rX43xMkRYHe3v5bt7Lu3r2fm5t/+/bdu/cewHTn7v3s23czs27fvnMPT3e8pfz8gtu372ZmZt++fffBgwclJSUjIyMGg2HPegtNkDRB0gTpFe8/QSLDQpzV8EDHwMMiH7+dJsg9BrX+UCna1UMNi/TV+1U8V58BTif5+PETH59vg4ND4+ISYmPjwy6EX7gYgafIqJh1KTLaLV24EB4ffykiIio09EJISFhoaOjFixfLy8vVajVNkDsBTZA0Qe4c7z9B4pY46BtkhvMmgqSwM200Qb47QNe7EEaj0Wg0WiwWu91utVqRxpUgCLT7iyyQ90uIRG+bJCmbzfHkSVlcXEJ7e+fw8OjAwFBPb39Pb39v30Bf/+Dg0MjQ8Ghf/+C61DfglgYGhoaGRoaHR0dGxrq6Xj5+/DgpKenmzZtsNnvPjs/SBEkTJE2QXvGeEyRYL5EATOkKPPYg8V0fmiDfKSjXHrBUKh0aGmIwGA0NDXV1dc+ePWtqapqbm1tdXUUR0JaWlgYGBkQiEfL9vY8lR2stkqQsFqKwsDgtLZ3PF2o0qzKZQq5QyeRKqUwhlSnkCpVSpZErVHhSeCSZTCGTKVQqjVar43L5DAYjMTExKipqbGzsbR0rbhs0QdIESROkV7zPBOkmHbrxHHDpWgGmdIVxqdBe15vuRU7vPAkSp16NRrNzgtxHdeK7A+WyymGxWFVVVdeuXUtOTr527VpERERgYGBRURGXyzWbzUqlsqenJyMjIzQ09NWrVzDI9j467aOodRKkxUI8elSamJi8sLAkFkt5PIFQJBEIxTy+EPIEz2Py4vOFbonL5cNpTiSSLC6yXrx4ER0dHRMTMzk5CV3z70m9aIKkCZImSC94nwkSwm1PC2pcoSE+Oq+GzCNRRBGKopAlIekKZmS1Wi0WC+VyGwu8sRfKiKIorVY7ODiIjnlsu/zvX5dFrSSXywcGBmpqamprazs6Om7evPn1119nZ2eLxWK1Wv3q1avU1NSjR49+9NFHz58/JwgCnT3dp2L/8JmigNVqe/So9PLlK4uLLLFYyuGs8AUinCD5ApHbxMTzliCdiMVSNnsZRlKLioqamppCc9a7Bk2QNEHSBOkVHxBBQhAEYTKZYGBbo9GIm/DAKw0Gg9FoXF1dxY+ywSBcFotFq9Wura1ZLBZ0AmEPCHLnjXDQgKRAm82m0+mUSqVKpVIoFCUlJUeOHGlqajIYDDKZbGRkpKenp6ys7LPPPnv69KnRaITxLvar2J4EWVRUkpKStrCwJJHIuFw+lyfg8YUbSJCe7Mjl8ldWeDyewI0gJycnaYLcCWiCpAly5/iACBIAYLVax8fHKyoqrl69Gh8fX1JSsrCwYDab4QRhs9nm5+cfPnyYlZV17dq19vZ2rVYLAHA4HHq9nsFgZGZmxsfHZ2RkdHZ26nQ6sCcS5HsJ1G54A66srNy+fTsoKGhxcREAYLFY5HK50Wicmpr6+uuvy8vL4boE7N8Y9iTIwsLi5OTU+flFmUwhEIjgLPxWBLm8zOXxBEKhWCgUT0/P1tTUxMTEQIKEPXMP6kUTJE2QNEF6xQdEkE6nU6lU1tbWXr16NSQkxNfX98yZM1euXGGxWCRJrq2tDQ0N5eTkBAUFXbhwITAw8MKFC3V1dQRBGAyG9vb2uLi4kJCQ0NDQoKCg4ODg9vZ2FL0Pz+7dESQSc9/0/ZsuOLDAhXsAQGVlZWhoaElJiUajQZ4BSJIcGxs7dOhQRUUFVHqDg0SQjx8/SU29PDe3IBJJVlZ4bM4KmojhxLopQUIu4fOFAoFoamqmtraWJshdAU2QNEHuHB8QQVqtVmgzOTg4KBaL9Xr9/fv3f/GLX9TV1QEAxsfHY2NjL168+OLFC51Ox2KxoqKifH192Wz2/Px8bGxsfHz8ysqKyWTq6+s7fPjw1atXpVLpQSBIcj3+Vvo3Xk6KoqxWa3x8/DfffDMzM4N+JUnSbrf39fV98cUXZWVlFotlf01Yve5BpqSkzc0tQCMdFnuZs8x9K4KEHLmywhMKxYuLrLq6utjY2OjoaNpIZ4egCZImyJ3jfSZIpMSDsghBEBaLZXl5WaFQwN5QVVX105/+tKqqiiTJgYGBQ4cOBQYGstlsu92+traWnZ194sSJoaGhurq6iIiIhw8fqtVqAMDCwkJkZGRkZOTAwAA8tEe5zHbwwLkAAKVSOTIywuVy0W7ltud3XA5GUXlhyC2r1QpjQaPDglDSQqzsdoLlIABpvOEHh8MhEAjCwsJ8fX2lUil0kAuvdDgcIyMjf/3rXysqKoxGIwBgf13NUdT3Jz1IkjKZLI8elaamXp6dnReJJDyeYHmFB5NXdtxgqlpe4QlFkoVFVn19fVxcHCRIeg9yJ6AJkibIneNDIUjowwxKJCi2Rk1Nzccff9zY2EhRVENDw//+7/9GREQYDAaHw2E0Gl+8eOHv79/Y2JiRkREREdHd3Q0naKlUmp+fHx0dXVZWZjAYoDKQoigYhFkgEIjFYqFQKBaLZ2dnu7q68IDJ2+58OEGiow5Wq1UsFr9+/bqhoeHFixf19fWjo6MmkwleY7PZ4MR3AAkS+XyHb0ehUDx8+DA8PLy4uFin08HaIXesUIKsqKiAJsTQ0ni/QBMkTZA0QX44eJ8JEoJynWUELsEFzs5SqTQ3N/fYsWODg4MkSVZXV//yl7+MiYmBp7MJgqitrQ0PD3/x4kV4ePjFixeHh4ehTKZSqWpraxMSEh49emQwGNADdTpdR0dHTU1NQ0NDY2NjXV1dZWUlg8HACXKHtUDbdTBHsVhcVFR09uzZU6dOhYWFffXVV35+fsPDw/hZCFz1enC6PuU6bwObhcViHT9+/MqVKzweD7Y/tDeG/nQ6Ojr++te/lpWVQfthdNJ0n0pOEyRNkDRBfih4zwnS04AFzQUvXrwIDQ3Nzc2Vy+VOp/P58+e/+c1vEhMToakkIkioXw0JCRkcHDSbzU6nU6PR1NTUxMXFlZaWrq2tIVnHZDIplUoejycSiUQikVAoXFxc7OzsXFlZgYdJdlgRnCBhJ+7r6/v666+vX78+MTExPj5eWloaGxublZUlFouREIZ8fB80goSe5OC5mtra2k8//bSgoABRJkmSarV6amqqo6MjKSnpo48+unDhQlVV1dDQEGTQ/dqMpAmSJkiaID8cfCgECbAplSCIpqam2NjYzMxMuEFIkuSLFy8++eSTpKQk6PnTarXW1NSEhIS0tLSkpqaGhYWNjIxAFatKpSorK4uNjS0tLdXr9fD5KE4TktsAAFqttr+/n8vloqx3rmLFLXFqa2t/8YtfvHjxAl4jl8vv3r174sSJubk5yDQoPslBI0jYPlAJrFAoamtrMzIyhoaGAKYY12g0PT09JSUlqampFy5cSExMzMnJaW9vh1L7foEmSJogaYL8cPCeEyS53gW5w+FQKpUDAwNpaWmpqamzs7NWqxUSSUtLy8cffxwVFaVWq6E5T15enq+vb39//4MHD0JDQ9vb241GI0VRPB7v+vXriYmJra2tJpMJZgTnekRFUIBTqVSDg4McDseNPrcBxPQ4QdbX1//Xf/1XaWmpw+GwWCwKheLy5cvHjh2bnZ1FF4MDZqSDy/HQmZFer+dyuQKBYG1tDe4Ww9JaLBaBQDA5OTk8PDwyMjIyMjIxMbG8vGw2m/dLvwq8EWRKShpNkDRBvlPQBLlfeP8JEo/yaDQaq6urIyMjk5OTX716ZbFYoMcch8MxMDDw1Vdf+fv79/X1qVQqkUh0586dgIAAoVDY3t4eEhJy7do1iURis9kmJibOnj2bmZkpFoutVitw7ajhsiOccbRa7dDQEDSL3a05HZeGX758+cc//jEpKWlycnJubm54ePjs2bOHDx+emppCK4ODQ40QbrpuAIDT6YTGwMjcCV1pt9stFovZbIZO/qxWK7TU3cfqeCVIdMyDJkiaIN8FaILcL7z/BAmVjSRJWiwWJpPp4+Pzox/96Ne//nVISEhkZGRERERNTY1EIpFKpaWlpeHh4X5+fmlpaeHh4aGhofDsnUKhyMnJOXr0aHR0dHp6enR09OnTp1tbW+H2HnDRsFeC3HVPOngucrm8srIyNTU1ISEhPT09Kyvr+PHjX3755cLCgtPphIco9td5qVdQWJRHvLnwQrrxKKJ5ZNpzcIx0aIKkCfJdgybI/cJ7TpAAUzDa7fbZ2dn8/PzLly+npqampaUlJydfvny5qalJKBRarValUtnZ2Qm1r5cvX25oaFAqlVB3Oj8/f+/evbS0tLi4uFu3bjU3N8tkMhj6AwCAh5x81wSJNhdhRgRBDA4OFhcXP378uKqqKiEh4eTJk2w2GyowcTezu5L7boFynb3x9GeLFxgxIiLIfa8ITZA0QdIE+eHg/SdIJILAMLzQEblGozEYDDqdbnV11Wg0QhUoSZJWq1WtVsvlcoVCAUN8wCcYjca1tTW5XC4UCrVarV6vR6fxkHwD/3UjyIGBAQ6Hg+hzF+VIKITZ7Xaj0WgymaxWa29v7+XLl69fvy4WiyGDosOX+97pvZYBtRvlDbhXBPwh+6s0pgmSJkiaID8cvP8ECYF4C20HIgUpZBEUD5LEIkHCyyAPEQSBjt7DrUer1erGjuDNBAl/3ZXOB/fqAAAGg0EgECgUCp1Ot7y8HB8fHxQUNDAwAKsAK3VAVKyeYiJubbQp5+17+RFogqQJkibIDwcfCkHuGTwJcocBk91AYcFJZDJZVVVVbm7uo0ePCgsLIyIi7t27J5FI9tGMxVPIg/86nFYnSThJwuG0AuDYVloH3PwKzwg1zrurIFxLkSRpMpkePXqUkpIyNzcnFot5PB5NkDRBvgvQBLlfoAlyl/HuCBJxDwxFCQAQCASlpaURERGBgYFJSUnl5eULCwtIzPWUbvcAbyJICjgo4CApu8NBOJ02inJsmgBwrk/es0N2WDRB7qRSNEHSBOnKiybIH0AT5C7jHRGk284c3AGFXkxFIhGXy+XxeKurqygj3G5oL/EmggTg++R02knSQVFOknRsnCjKuT6tg5vPBEBLkDurFE2QNEG68qIJ8gfQBLnLeBcEiVMjeg56JnJNQLrctO7jQYg3EaTdTiBepCgn4ss3JQ92dCdInA4RU9IEue1K0QRJE6QrL5ogfwBNkLuMd0eQ0KQTPcotU7TvuN/HBL0TJDpzAquAnBjsHPCB0BaJJshtV4omSJogXXnRBPkDaILcCF49YuM6Pc9fkShDUZRGo9ktgiQxjwcupeU6W1Cclty0jtvIcdtwE/LQN7AFTCaTXC7ncDjLy8srKytcLndlZYXD4bDZbM56wAvcsLy8jN+4tLTE4XC4XK5EIoFRPsjNrGF3pXaI3c1mM06QXC535wRZW1sLAyZPTExAt+zbK+RbNcJuEeQPyYMgJyamIEHu2fT7LghSLldm3Lh16uTpvp5+k84I7HtRGYr6gSCzs+/QBLmXoAlyE1Cus+pQTMENRL1yD4n5YlWr1bu4B4nrEvHn4PrGA9K5PedoGFdkbm7u8ePHly5diouLS0hISExMTEhIiI2NjYmJSVyP+Pj42DcjLi4uJiYmIiIiPj4+KioqIyNjaWkJndt5pwQJsAhiFotl1wmypqYGNsjExATy9Pu2hdwvgtxAgtwvgoyMitltgrx56uTp3td9e0+QHM4KTZB7DJogNwKFGYLiYtkGOsx3TZB4jA5cRDuYBIngdFIEYRsYGMrMzL5/P+fJk7KysoqKiqqKiqry8sry8kr4eYNUXl5eUVFRUVFRXl7+9OnTJ0+ePH/+vLa2Njo62sfHp6ura21tDSpakf+gd1Ev8DdCkNu4ZScEyVnm4rcsHwCC1BuMhUUlSILc+huhCXIPKvW3ApogNwdiRDfloVe8a4J0uPC3RZAUBQjC9vp1b3b2neHhUYlEJpHI5HKlXK6UyRQymUKpVONJoVC5JblcLpfLlUqlXC6XSqUSiUSv11ut1tLS0qNHj5aVlUHnR3AN8SET5PbqtVsS5PefDxJBtrZ1SKTybbAITZA0aILcCIjqbDabUqlks9lLS0vLy8sqlYogCK+37IGK1U3RemAJEom8TqeTIoHd7hwYGM68dXtwYITLFQgFEolYLhHLRUKpSCTl80V4EvDFQoFkXVoPPp8vkUjkcnlubu6hQ4cePnwoFAoJgiBdDvbexebr3xxBbnGhsHOChBX5oe5c/v4TpN5QUFgcHhFFE+TbEqSX5e2HCpogNwLlso5hs9n37t3z8fH58ssvT548ef/+fRaL5fWWd02Qnk/4myBIQAHC6ujvG87KvDs2OrmyLODzxEKBVCiQ8nliHlfkmfg8MZ4gKfJ4PIFAIBaLhUKhWCyWyWR5eXmHDh3Ky8vj8XgEQVCYBdO7qBegCdJb4gtEK1w+m7PCWeZyeQIeT3DQCJK3LSKhCZImSBpvBOwZOp2uvr4+LCzM19f33LlzZ8+e9fHxaW1tRW5OocgCWZB0HUYkSVIul/f29sJ4kPCBbnpa1PO8GuCQmMEqfKbXJ2ylNyPFI6oX/IwYxVMkxeHmS5Za76PH8wl4pb7/hgJWi6Ovdzgr897w0DibxeNxxXyehMcVrywLeVzxskCyceJxxXgS8KVSiUoqUT24//DQ518UFz3hcrkwojUypNpiQyGnCpuCxM7wQIIsKChISUlZWloSi8VsNntlWchdEQkFMrFIIRTI+DyJW3KrBUx8noS7IpJJ1QvznBcvXsTHx8fExDCZTBRtdGMgZ8Ju74hy+V3aYjusra0xGIySkpLu7pd8vnBlhcfhrPB4guVlLpyLf0hcoVsVVpaFqIJ8nkQolCwvL/P5/Pr6+oSEhNLS0vHxcavVuvVXQ2F9DFebb1wLymVSBwCwWKyFhcWhoRdaW9slEplAIOK6RFvIKzyeiMsTb5zQ2+HzJBKxUqPW37iedeq7c69fDVjMDrtt3f6L10KiUUy6PHigEU2ttzzH34XH+AUmk2VxkZWZmX379t3x8UmZTMFmLwsEIh5PwONL8OS1Fnjirojg++Kw+Q31LVfSM2pqaqD2BR8RnoYOnuUkXW6f0Wvyavn/twuaIDcCfN/j4+NpaWlJSUnz8/Mikai3t/fbb79NT09fXl6Gft1Q0Az0Fw4VlUo1MDCwvLyM+tCbBoDnpICGuk6n02q1a2trarV6dXVV9/ZYW1uDf9fW1lZXV1dXVyEvwgGwRW/mlAe5epbfszo/DCcK2G3Ogf7R7Kx7gwNj3BUhnycRCmQCvlTAlwgFshWBZOPkOSPLpGrdqqm4qPQvfz5cXPRELBbDAGRoMtoUXnl900ZAf61W6+PHj1NSUlgslkQi4fF4QoFUKJCJhDKRUAZrtylBCgVSkVAuFMjkMvXiAqeuri4mJiY6OnpmZsZisWylYKjL4ZXCZ+EtPmFtba2lpaWkpOTVq9cymQLKKAKBSCgU8/nC9UnkVi+hQCYWyUVCuVAgFYsUYpEUCvo1NTUJCQllZWWQIN+qtcHbvyC8viaTubj4UWRkdGdnt0qlEQrFSOTi84UCgYgvELtRi2cS8CUCvpTPEwv4UolYqdXor1+7deq7cwP9o4SVtBHropmiYe5ZJNLl5WPT2G2eYwdeZbc72OzljIxb2dl3RkeZMplieZkrEIgEApFbmfkCqVsS8Ncl+MpEQvkyh9/Y0HL9WmZ9fT2M4oBmoY2bHf+J8kbzW39fBxw0QW4Ep9NJEER5eXlwcHBVVZVerwcACIXC9PT0S5cutbS0QCUY6fJog/5CgtRqtSMjIysrK3hsLK/w2iMJglAoFI2NjQUFBeXl5WVlZU+fPi3bDE89AL+HT3j06FFVVRWHw0EOXbcoYeARu6j1mkZP8RdNBEjLCihgIxy9PYN3bj8YHBiViBVSiVIuU8ukKplUpVRoxXLVxkkqUeJJLJLrVo0Ws72o8PGhz/+al1vI4/GgyOUZh3nTZt/KxXjt4GebzVZWVnb16lUul6tSqeRyuUyqgmVDya3YnkkuUysVWqVCq1KuriwL2traEhMTY2Njp6enodZriwXD5S28+lt/gkajaW1tLS0tffXqtUKhUqu1kCahFdW6JFXCF4cSfJUioYzHFQn4ErFYqlKpNBpNfX19YmLi48ePp6amYPQbFMJs0+qgjrTx2PEE9MW4tqYvK6tISEhsbW3XanVqtVYqlUulclgFuVwpkymlMtXGSSZVKeQaWEeVctVitt+6efvkiTM9rwcIq9Nh/2EhS71BgqSwboYu8Bw1bhfjgKPPYrFyOCv37j0oKiqZnJxWqTQSiUwqlcvl7rWQydVuSS5bl2C31KjXBHxJQ33z1SsZNTU1aPmCj9wNGhnNdZQr9CyauLa+Qj34oAlyI8DukpWVFR4e3tfXB/uQTCarqKhITk5+9OiR0WgELvKwWCyrq6symUwul8tkMoVCsby83NXVxWQyoTmJUqmEv7pBJpOh7xUKhVwuF4lESqVyZWWlo6Pj4sWLn3322ZEjR44fP37s2LFvvvnGZ0Mc88A333wD7zp27NiXX355+vTpqqoqHo8nEokUCoVUKn1TYRCUSqVEIoEXw7sUCoVMJpNKpVKpVOYCqgL6F1ZHKpWqVTqlQtvS3JF4KfVy2rUH9/NzcwrycgtzcwpyHjzMyy18kL9Jys0pcEsFD0selTwNCb7450NfFDwsmZ2dFYvFqJG9NrUnxGKxVCqFZd7K9ajFYJtkZ2efPHkyKysrJyfn4cOHebmFqFJek2ct4C0w3c6+n5ycfObMmZiYmMHBQYlEAqOTbgzU1NC4VyaTqVQqeKNMJoN2v5s+Qa1W83i8qqqq+Pj4hIRLOTl5hYXFhYXFubn5eXkPc3Pz1yf3ity/l+aZyrkAACAASURBVIfqmJdb+PBhYUFBQW5ubnh4eGBgYFFR0eDgoFAohL0F9qVNi6RQKCQSCRwLW6kFei+Qm3k8fmFhcVjYxaSklIKCooKCopycvJycPFijvLyHuXkFObmbpNycgvy8IvhO8/OKiotKfc/6H/f5rpnRLhLK5DK1RCKBbf6mGsGxoFKpVCqVWCyGbwoCldnzehyQCMVi6cjIWEpKmr9/YEbGrYcPC3Nz83Ny8vLzC3LzCvHktRZ4Ql3x7p2ctNSrUZFxT548gYHzYDtv8e3AsWOxWLwG1dnnuXuXQBPkRqAoym63p6enh4SEjI6OQstVhULx/PnzqKio0tJSKFOi6IxLS0vj4+OTk5MTExPT09NDQ0M1NTXt7e0TExOTk5NTU1Pj4+MTHhgfH4d3TU1NwW9GRkbGx8dHRkagX5XTp0/7+/sHBAQEBQXBvxsjeD3Ql0FBQX5+fuHh4U+ePBkeHoaFGR8fn5qampychMWGhXEr4fT0NLysp6enq6trfHx8enp6YmKCyWQymUz8FvScycnJ6enpmZkZeOXExNT8/GJra/vNm5mhoReCg0ODgkKCg0MDAoL8/AL8/QMDAoM3SQFBeAoMDD53zi8gIOjcOb/w8MiqqudDQ0OwMNPT09PT00wm07Op3TA8PNzT0zMwMAALvOn18B3BJ8M2ycrKOnXqVGBgYGBgoL+/v79/YEBAEKxaYGBwQECQv38gntxqASuCfvXzCwgJCYFhy7q7u+Hr2LRUEFNTU/39/S9fvuzv74eND9+Oq/03ApPJnJ2dnZqaqq6uTkxMPHfuvL9/4Nmz586f9z979ty5c35+fgEbp7Nnz/n7B4aEhIWGXggLuxgSEurn5+fr63vixInw8PCysrKXL1+OjY2NjY3BBtxia8P+Njo6OjMzs5Xr4d+ZmZmFhYXR0bHi4keJicmhoRdCQsICAoLOn/c/f94fFhi29vnNkp9fAHyJ8EbYXZOTU9vaOpjMiampmcnJSdT/vXY5OLTn5ubg8Onr6xseHoYvCI13t1q4YXSUOT4+OTMz198/ePXqdR+fb/GeExAQ5DZS/AOC3JJblwsKCgkMDD579pyv7/nw8MiUlLTq6mo4CcC/sGzw85uaem5ubmRkZHBwUKFQgANpKrgroAlyIzgcDpvNdvXqVX9///HxcbiPrVKpXrx4ERMTU1xcrNPpKJdViNVqFYvF0FMam83mcrmzs7NtbW0wZjL0kebpU43tAvoXeV9bXl6en58fHx8fGxuDfydcBIaDuR6eF+B3wWvm5uaQwza8SHhJvJazr6+vpaVldnaWy+UuLy9vcD3uE47NZrPZy1wuf35+cWhopKOjq62to7W1vaWljcFoaWpqZjBamlvaGM2tTYyWxqbmJkZLE6OF0dy6LjFa8NTS0tbYyGhoaGIwWl696pmZmZuZmZmdnZ2fn4f+57wWyQ1jY2M9PT3Dw8NLS0uw2TcGvAt+htczmczOzs7Ozs7W1tb6+vq6uobGRkZzc2tTU3NDQ1NjI6OpqXnjBC9Gn5ubm1++fAkpYXFxkcVibVoqVLbh4eH29va+vr6lpSU2m81isZaWlrbSFCwWC77Kubm5wcHBrq7utraOmpq62tr6+vpGBqOloaFp41RbW9/YyGAwWhobGXV1DXV19XV1dQ0NDQ0NDR0dHRMTEwsLC7A8sNtssUavX79ubm6enJzk8XibXg/fCIvFclWHMzU1098/2NHR1dzcCnsLSvDf+k1TfeP3V9Y31tc3VlfXMhgtvb398/OLLBaHzV6GHhBhvtD3oRtYLBYcCAsLCz09PT09PePj43CYQ3jWAn81Kysry8vcpSX28jJ3eZk7MDDU0tIGa4SGDxwvKLkPnObWZo8E31RTU3NHR1df38D8/DxsYVgXVIY3NTUs/9jYWEtLC5/PB+v3WWmC/FDgcDgIgrh//35kZGRvby+UFJVK5dOnTy9fvvz06VMkQVKuzRWz2Ww2m41Go8ViUSgUAwMDCwsLOp3OZDIRBGHxgHk9TCYT+t5kMlmtVoIgCIKw2Ww2m81ut0N3dzhsHrCvh9v1drvdarWazWaYi9FoNJlMJpMJFsCzhKgwZrN5fn6+u7sb6lVQ4WE53apjsVjgl65KETCZTBa93gj3hPCkXV1Ta1aVKo1SpVGptSq1Vq1ZXZfWX6/RrGpcX+p0epPJAq2QDAaD0Wj0WhezB1ZWVsbHx1ksll6vJwjC84KtANpPudTOCpVKo9GsQgcIKpXGrdieSalU45+VSqVWq0UvBTXsBoAtbDKZOBxOX1/fzMyMXq+HHcloNMJ3vTFMJhPK0WAw6HRrarUWunGAXhrc3Dh4Jngl9PAgkynk8u+VdbA6BoPhbVsV1n1mZqa3t1csFm+lHWBNTS5YrYTVajMazVqtDpbQ3RmFR5IrVG7JzVuFUqnWanUGg8loNOv1xrU1A+rkZtcYcQMcwmazWaPRzM3NzczMSCQS+L3FYtl0TrBYLHDUGI1mOHZWV9e0Wh3s/CqVRuUaLxskz14Hb9RoVtfWDK7hshE8S2iz2VZWVhobG3k8HqAlyA8TkPYeP34cEBDw9OnT1dVVAMDKykpSUlJ6evrIyIjZbAbrz2PgG/VarXZoaIjD4UBjV+DNpPBNG+AUZqewlT3ztwJuKIGb1W3QFLAwbDa7q6tLq9V6FtitOvg3JEniETwAtlFBYTsWXk1+EN70K27LgOfouQvi2Q5SqXRychJaUW27MfGFMx6PE3k72hgwa+DS59tsNjcblk17KcpFJBKNjIwsLCxAK2WAmVFsDLxnUt+3HoBnFp1OiiDsJEmtT+5ATYH/C1djWzxC41kviqLm5ub6+vpkMtlW2gEvP/5kkqQcDtJmc7jVwkmSTmqT5FlN9NntSMMGVYM3Wq1WDoezsLCgVqvRLRtUgVy3q/f9o5zO7xN8Qd+/o7evBYVZdW2xh7h1OQCAVCplMBjLy8uAJsgPE3AADAwMJCQkREVFQWVpTU3NiRMn7t+/r9froXkq3o1wozutVtvT08PhcPCjQhvniHffN9nvvW0tPIcrFCWp9SaOmxYMALC4uNja2qrRaDbNC/8Gn1Dw6dKz1luH2zjctGG9QigUjo6OstlstILZIdwmnS3e4gZ0BG2Lp8rQexQIBIODg3Nzc9BeFLxNs1DrCRIAAG+lqO9n4fXJHZ5PwyuyvbZ1OBwzMzN9fX1isXjrT8B6yPdEAsvsWQuSokiwLlEAuCU3kJgzZDy7TcsDACAIYm5ubm5uTqVSoZ82vQu4XgF8HYga8VvdauGZ3vS+3vT6NgXsIXK5vLW1lZYgP1zAN726utrY2Hjq1KkzZ874+fmdOXMmLi5ubGwMYHMT6hN4YEIY7gqXIN+09EZAc4pb6MeNqcLtgZ61cLse9+aKBDtUC89nAtfUz2azX758qVarvVIamt/xX3Gmh0DXuH2Dl9xrvTaG55WbPoHP509MTKysrEDzq02z2DTrjc9Wb3C7243oZK1nh/HaheAT+Hz+0NAQlCCdruibWywJepRrEQOQR1tvycvtlLsM+sOSaCuvz/OBdrudxWIxmUyZTLaVdsCzdj3mhzID4KUW26AWz+batH/CgplMpoWFhcXFRTh80OyxaS+F74Ik4fr7B4L8gem3S5CoxbbyOtwKCQAQiUStra18Pp/ElvUkTZAfDuD84nQ6NRpNT09PfX19Y2Nja2vrzMyMwWCwYPFsUZ+AkhkcNlqtlsvlymQyqGjaSo6kNwkSZeG183ntu5vmgiS5rcsoAAClUrm0tGQymTbOyO0nzzHpRoekN4J805D2rAuaH98Wer1eKBQqFIo3HfHeFG4FI9dz/6bzjlv7o89v5Y4ECZoajWZpaUkkEqEybP05qCKuKvwgQcI3szFBwmPmeK0Bpl3fSvN65TyhULi0tARV+ltvEI8neyfIbUiQuOzo1m5vgtPl54ggCJlMxuVydTrdxrd4dvt18iKJ0ve6Ys9ib1wLz+w2u8R7pdbW1qampjQaDRQAaIL80IGbyXhVf+HERpIkQRCrq6tms3nb8y967PrRsq4jegofqGyUNwFx22Ww2+0Gg0Gr1e7ERygaSAAAkiSh7xtc3AEuKRyJuW78tz0u9CwGSZLIsALFknxb4K+bwiQ2+CvchAMAuDmNg7SxKxUBrtkKVker1er1etieb7tuoNZL4fiXKAt4JBw2F4WdEEcvC2og3fQf2ygD7G9ra2sajQbtZWx6rxvcLsCLir6EpumkSxBHf/Ect9GYbvdCYzqLxbK2tmbBHCRtY0h6UhH6Bl91oa4IN6SREgupiPFFzDbKAACw2WzQvddu9eQDCJog3wL49PEmvkEDCc4mcPLdITOhD3BuwiMDw5EMV6ZarRbm7mmDs0OCRCPQbrcTBLETvnd7FCJy9CUkFbeZDomYu0Ut6FFwxeMmv24dTqcTBaFE7x157YK/OhwOmUym1WrRXIx+3eHKCQJ1BrvdDs0j8Xlziw/Bp103goSAsyoytoLGRACT/tHrw9/XWxXDbeqnKMpisUBz1q28ccoDbhegLXCAORG12+1isZjP51ssFti1IDXi7iGpHRAkegjqb26mPTt5IN5WnmMcDjHg6iH4AnTnBAm7hMVigWvc9xU0Qe4y3OZ0ZAuzbaDuC4cuTrckSRIEweVy79696+/v39jYCFy9H20xuo2ibZdhh7VAwCdcOMlarVY4c5lMJuinY3V1Fd8ixctAeuxfbrsYJKYS3PZzIL+SLjNdgPnkQ7MSm82+dOlSdnb23NwcnCIdm/nmfSvgKzZ8Ht/6W/OkFtRb4AckTjmdTovFAt30mEwm+BLRQ3DVBd5Lt01vqPfupBb4A5GJAByYNptNLpdnZGRcunRpbGwMLj1hjRze/OFtpRh7AzQWnJj7OvgBLqPhyFKpVFqtFr419CodHtFkt12A3a7WgQNNkG8Nz5nI8wLESeR6bKMvehIkGhV2u10ulxcWFv7hD3/4zW9+k5qaOj09DWdq3Lx+tyRIz8/bfhQanEgjp9FoGhsbr1y5cu3ataqqKqFQiKZIdLFbg+wE1HqV1LYrBQnPTa4lMTOomZmZ9PT0I0eOfPbZZ0+fPkUCPS7N7BAwL0/bKJyJN4ZnU1Drl1awana7XafTdXd337hx48qVK6WlpSwWCy0RyPVmMviL28orw3sp5U082vQJbyo/zrL406xWa09PT2Fh4bFjx44cOXL//n3o9wNpYt2KtL2XRXooQp27cZqeejNBUhTlcDhmZ2cLCwuvXr1648aNzs5Ok8nkddtlh2VAD9zJcw4yaIJ8a+DD703XICnHre/uSr7oXw6H8+TJk5CQkKioqMzMzJCQkPz8fKiPwrUoB5wgAQASiaSkpOTbb7/905/+9Nvf/vbPf/7zkydPoDU8hbl4Bm+2VNpGMXZl+kNqUhKTd6G8RRDE0tLSlStXgoODCwoKjh07FhcXp9Pp4H4k6drP22FFwBustCiXUnTrT8AbmcIMqinX3qrNZmtubj5//vz//d//HTp06NChQ9nZ2Uql0okdSsE/v9VSxq0MpIe506ZP2JQgkYgPANDr9aOjo9HR0T4+PmlpaRkZGUFBQcvLy0g9TmJnc3fY4dEHcvcWRm4LCGq9BAm9BH/xxRd/+ctfPvroo7CwsL6+PujVBHh0/p0UY7fG44EFTZDbhNe+5TY48elmhxnhT4ZSi1wuh6RSXFwsFovn5+eDg4OjoqIkEgmyIaI85KRdqawbyW3xsZSHbEG6BK+BgQF/f/8bN24sLCx0dXWFhIQkJCT09PTodDpIJG4Nu/OtO7c5BWxX20l5I1r479zc3OXLl8PDw5ubm9lsdnp6enh4+MjICDzVtyu18KwRXp2tz1ykh+iGvyzgIhWRSASDOQ8MDLx+/To5OdnPz6+5uRmaZUK1Hm6tgz/2nZbf8wlucGKR3eAu/sTERGJiYnh4eG1tLZ/Pf/r06cmTJ3t6egwGA+J44CFbb70wG5cQ/2bbD3FrK2Q/z+FwysrKkpKSnjx5MjY2VltbGxwcHBkZKRaLod6V2jFBUhjr77xZDjJogtxNuE24b7WC3grQMwmC6OzsTE9PLykp4XA4AACj0Ziamnr+/Hkmk4mfP9n1MgAPgtxiFpQHoaJpq7GxMSYmpqOjAwCg0WhqampiYmJycnIWFxfh9gl+MXWQVDoktvvowCJmr66uNjQ0XL58uaamRqvVWiyW2trahISEBw8ejI2NoZXBAakItV7KgS2MTKggLBbL+Ph4dHR0SUkJtDYaGhoKCAhIT09XqVTIZtKrZnJf5lAKC0RFuXTOsCRisfjRo0c3btxobm5Wq9UEQfT09ERGRhYWFq6srHiaT2+Drd8dNlgHAABIkuzv779w4cLdu3c1Gg3snDdv3jxy5Mj8/DzAovJRmA38/tboIIMmyN3EuyBINLzRAICT1/T0dGdnp0KhgEohm81WW1sbGhqak5OjUChwbdKuYxsEiS6GcxaydSRJErrc7OrqgvuODoeDz+dfv349MTFxdHQU3QXlSLRMfhf12gZQYdA7glSh0WiGhoaGh4ehXzGHwyEWi7Ozs318fJ4/f478yR0QC0ByvVIUsT7qe06n02w2C4XC169fLy0twSt1Ol1aWlpoaCjauqNcel2vc/fewC1fEjOyBS56EIvFfX19c3NzMBIFNDMuLCw8d+5cW1sbcCnJHVhg0YNDkKQH8MpSFMXhcCorKwcGBpClQnV1tb+/f29vL3SNCTx2Lmi8CTRB7ibeEUGizwRBaDQaoVAokUigY250DUmSQqEwKyvLz89vcXERFmMrp8e2V6TtVRPtvthsttXVVRgMT6fTQetBKCmSJKlWq+/fvw9jItpsNo1Gw+PxFAoFvux9F/XaBtDGG2xqm82mVCp5PJ5Wq7VarSaTCc3RAIDS0tLf//73cGmPn6zfd5Dedg3h5At9KYhEIvimrFYr3Dp1OBx6vf7OnTtBQUFwt1ilUi0tLcE+iWvF954gkR4efobnN5xOp9FohCEz1Wo1PFuJPIEAADo7O3/7298WFBQAzAL5b4Ugna4DRdD4AAYkgMsviqLa2toSEhLq6+stFgtJknw+X6lUHpDF2QEHTZC7iXeqYiVJUiwW19XVJSYmxsfHt7e34wf2KYrS6XTQJK+/vx8N7F0sAJ7X9iRIdKVSqWxqasrIyMjMzOzs7MTDasKKwCDVc3NzJpOpq6vr9u3bLBYLHggB70ZvvD2gMgMAHA7H1NRUTU3N5cuXi4uLORwOYkF4QUNDg4+Pz+XLl2dmZg4UQVLrdxzRN0ajsbOzMzk5OT4+vqSkZGRkBC5ioKRoNBpv374dGhoKnfgPDAwkJycPDAwA12mKvSdImBe+ZAGu8382m43FYhUUFAQHB9+8eXNsbAwNH3glk8k8fPjwrVu3VCoVWi4cQIL0lM4pijIajUiZ5LbKAQC8evUqJSWlqakJmouXlpbW1dVJpdKDttw8gKAJcjfxjiRIuBxeXV1lMBjx8fG+vr6HDx+Oi4ubnJw0Go1ILLNarU1NTWfOnHn06JFKpXI777yL2AZBIvUjSZJyuby+vv7SpUsBAQH+/v5hYWHFxcWLi4vwUDOUTrKysoKCggYHB1++fBkTE5Oamgo3h9zm8X0HUtw5nc6hoaHMzMzY2NjAwMCAgIDU1NT29na4Pweba3p6Oj09PTQ09MmTJ1v3PrgHQFM/kkUAAHq9nsFgJCYmBgUFnTx58rvvvktISGAwGFKpFL4Ig8Fw7969yMhIDofDZDKTk5PDwsKGhob2UcWK5HW0MQx7i9PpXFhYyM/PDwsLg2GcL168WFVVJZfL4X4qAEAgEKSkpMTFxTEYDLPZDB3Q/E0QpFqtbmhoyMjIGBkZsVqt+D497Hu9vb1ZWVn19fWvXr168uRJRETE48ePYYwU6iBtWBxA0AR5IIAv4UnMdoPCtgo6OzsTExMfPnzI4XA6OjoSExMfPHiA9JMAAJIkWSzWjRs3QkJCoC91sBt26m9bEcToaIYiCAKFPVGpVE1NTSkpKVlZWYODg4ODg0lJSX/+85+jo6PZbDY8zmwyme7evXvy5MmrV6/GxsaGh4dzuVy3KuxNjdxmItLlZgVgDt7gZ7lcfv36db9z55+WPmEvsWqra747cfLrL796VllFOUmHzQ4oYDaaGAzG2bNnExISLBbLO1KAbw/4+3I6nIACC3PzYSGhcTGxEpF4fnau8GGB75mz3504+ai4RKVUAQD0ev3Dhw/9/f3z8/NjY2ODg4Onp6dxoQQ12t4saKDYB1DfoADpcDpsdspJWkzm4sIin2+OMRqbdNrVFkZzWEjo0SNH7t27B13VkyRpMpl6enoCAgISExNhAFeA8eue1cKT/9yOhSBPdUgDDK2lfvWrX0VFRTGZTEjtsHfBC0ZGRq5du3br1q2jR4+eOHGisrJSJBJR6z3o0vAKmiAPBHCCpLB4jcDVxTUaTVZWVmpqKlyhczicO3fu3Lx5c2pqSigUKpVKOMjX1tbq6+sDAwOhrQGJ+ZbcY0ZBmyJI0IQjls/nZ2Rk3Lx5c3h42GKxGAwGFouVlpb2ySef3LhxQ61Ww7pnZ2f/5Cc/+fWvf33r1q2xsTHkPg3PaC+rgxoQ9+FHURS0mzcYDGNjY1lZWXeyb8/PzlnNFo1KzWhs+uL//nr8mA+jscmwpgcUcNodCwsLqamp8fHxarV6L0WrjUGuNzp1OpwGvaG5iRETFV1ZXmEnbBaTWSaRvn75Kiwk9Pgxn6rKKr1eb7FY8vPzf/nLXx45ciQ+Pv7Vq1cWiwU/57fHBAmwLWFIaTYrAUiKsBLzs3N5OblxMbFzM7OAAqsa7dDAYEJ8/NGjR+Pj46F5J0EQSqUyLi4uJiYGt8vFB+YeVGFjgkSd0Ok6cet0Ouvq6uLj49PT0//0pz8lJSXNz8+vra2hYzZ2u53JZIaEhHz++edBQUGPHz/mcrlwAxIt7/agXn+joAnyQIDCLAvctDpwoBoMhtzc3JCQkNzc3L6+vrKysoCAgK+++urSpUsXL17MycmB2hWHwyGRSBgMBovFAm84l/muK0K5VKmUN58di4uLCQkJ165d6+vrg1HvoXnnsWPHjh8//uzZM2ibXl5efvz48ejo6NnZWeBSFLtx1R7AbarCfZrDesGJBm6UpqamZmdmzc/OOewOq9nCHB0Lv3DxV7/8/0KCgtksNkVSDptdp9ONjY319/fr9fqDs3hHC5rvJTCSspotXR2d4RcuFhUUEhYrlCkBBfp7+wL9Ay5euMhkMk0mU1NTEzzA2t3djTvp9Zzl96YW65qUAk67A1DATthYi0vZmVlREZGT4xMOu8NhdwAKMMeYERERn332WUlJiVarhYUfHBx8/fq1wWA4OPI9PnxID/8JTqezqqoqPz9/fn7+6dOn58+fj4iIqKysRLolkiSFQmFeXl5gYODz589hsBew3mv0flXt4IMmyAMBnMPcFq1Go9FqtVqt1v7+/kuXLoWEhFy9evX06dNHjx4NCQlJS0vz8/P79ttvExIS5ufn4YCBxixIVUu5RNI9GAmo/AAA5KiTchkTmkym1dXVFy9ehISExMbGtrW1zc/Pl5SUpKSkVFdXR0ZG+vr6wuXt3Nxcd3c3m81GAgHAjC33iyDRhIKOykHx0Ww2i8XitLS048d8sjOzZqame1/33Mq4WVJUnJ522e/c+aaGxrVVHekkIQ/BYx4HZ+WO3MdAIw61Sk1YrKzFpejIqAuhYRwW22YlnHYH6XCureqaGhovhF24desWn8/n8Xj9/f0KhcJoNFKuUyvO3fNQ8bagsHMmDrtDr1tTK1VrqzqT0VT25OmXXxwuf1pGWAnSSVJO0mI2d3d3JyUlxcTEdHd3GwwGiqLgdgBaquIl37NauMGNDmG30Wq1PB5Pr9dTFDU7O9vf37+2tmY2m58+ffrNN9+cPn26qalJp9MRBCGVSlks1tLSEpPJlMvlnudw9qVSfyugCfJAACdFdFJQLpdPT0+3tLQwmUyhUGg0GmdnZysqKh4+fOjj43Pt2jWJRGI0GpeWlpKSko4ePdre3g6w2A5O1xF7RJB7MCPjow566QQAGAwGgUDQ398/MDDA5XLFYvHVq1c/++yz48eP+/n5+fv7FxYWKhSK/Px8Pz+/wcFBGJUChgnD6RAx034RJMA2umw2m0gk6unp6e7uhha2DAbj1Mnvvjly9PR3pwL8/KMiIsfHmPOzc3eybz+4d39pYdFmJeBjnQfsdDYsjMFgGB0dff78+fNnz2enZ6RiSV5O7unvTmVcv8FaXAIUACRlJ2xqpere3Xs+Pj5MJtNms8GjLBRmFQLWL/j2siKwewAAzGYzh81ubmI8Ki5pYTSvarR9Pb1+584HBwY1NTRqVGpAAZIkVSpVf39/dHQ03M4H6+3s3KJe7NeChsL0q06Xa8aurq6qqqqWlhY2m63T6ZDsrtVqa2pqAgMD/fz8mpqaWCzWo/+/ve/saitL0/0l995vs9Z8m7VmVk/39PRMlbuqXeUpysY2NsYEkXM0wUSRcwabnKPJOZpocjBBRAFCASSEkFDOOud+eFt7jgXl6p4uC9X0eT54IRmks8/Zez/7Tc9bXT01NYXSjvBPmZ4kyM+DJMg7Bvap8iRmbHNBp9NLSko8PDw8PDwoFIqvr+/4+LhIJLq8vNzd3fX29k5JSYE40PHxcXJysr29/fj4OG4M3euMrXyQ6WNCNl9uOEQLEqyK+fn5iIgINzc3Jycnf3//lpaW2dnZ3t7e4uLirKysrq4uFoul0Wja2tpiY2PRWR4nCJaiYKqZt139Db00pFSwsrICKaleXl7Ozs4lJSXr6+vrq2utzS2J8QmV5RVzsx/kMvnpCaO6siovJ3drY1On0RJ9zhZyfocpx+FwBgcHo6KifHx83N3cnRwc83PzPszMlpWUfnPvj+mpaUeHdIVMrtPq2l1TeAAAIABJREFULi/4tTW1jo6Oi4uLOGHqoppCE/Pxi145mgzIpY9hmAJMw+iYAD//V8Ehrs4uIUHBne0dk+8nfL19nBwcB/r6ZVKZWqWGlr+hoaE5OTnQlhmRPfapsDj2l2Vr/4JDM7mBcBlqtXpubi4tLS0wMDA0NNTJycnHx2dwcBBOk7DcuFzu1NRUZGTkgwcPAgICEhIS4EkhN5L+U4kAS5iEFguSIC0FyEDBcVwqlVZUVAQFBZWWljY0NCQkJHh4eAQEBPT09MjlcolEEhwc7ObmNj8/v7u7W1xcHBISUllZyWKxwDuEVjXxw82caAD/qtXqjY2NlJSU2NjYoqKinJycoKAgV1fX2tra/f39o6MjDocjEAjA1szJyfH09Nzc3ERHdcTrRC+TOanl5nfBHYYWY9HR0W/fvm1ubg4PD3/x4kVJScnONo1xfEI/ODxjc+RSmV6nn5maDg4MqqmqFvAvMf1/1+MbzJg59VNDQ4lUYrG4paUlNDQ0OTm5tbW1taU1MuK1w0v71OSUro7O3OwcJwfHiLDwqorKmanpspLS6Kio4uJiBoOBf6qaDZ9szmg38R29UW5pc3MzISEhOSm5ubFpaGCwuLDI4aW9r7dPS1NzbXVNoH+AsxPlTVHxxPuJtra2hISEqKiomZkZ1NSaOJw7sYNxwkHTYDCgNqI4jh8eHmZkZPj4+OTl5fX19eXn5zs6Onp6ejY3NwuFQvhbCGcUFxf/0z/9k7Ozc0tLC5/PxwkRCuRRR99l5tH9ikAS5B3D5BQMWhiHh4ehoaFxcXFXV1cqleri4mJ2dtba2vr+/ft9fX1SqbSmpsbNzS0qKiovLy8yMrKqqurw8BAzKrEhoHVlToJEI9Lr9WKxuLKy0tHRcX19XaVSqdXq1dVVCoXy8OFDqH0EPzCbze7s7IyIiMjNzeVyuSY2lsHwCa/cyZ5FvJ9arfb9+/eOjo6jo6MSiUQmk+3t7QUEBHz//fdpKamL8wt6nV6jUivlis2PGxlp6ZAbgmM4xCDv3IK8yWQ8Hi8wMPDhw4cLCwsqlUqtUp2eMDLTM55YP05NTlldXsnPzXNycHShOEeEhfv5+GZmZBwcHEAOCAoPY5/CbKPACAYrXExHR4eVldXI8IhcKtOqNddC0ejwSICf/3ObZ10dnZCd6+rs8irkVUBAQGBgIITr0KnO0ggS3oHL6Ovri4+PLygoODw8BDmqqakpPz+/ly9f9vb2QodOtVp9cXFRVFTk5eU1ODgIfdT1xrYzmDHXjCTIvwQkQd4xbq5AhUKxuroaHBycmJgoFothWp+envr7+//jP/6jr6/v0dERk8msra318fEJCgoaGxtTKBRyuZyoDID2C5SnY56lTmRHEFspKSmxsbHZ2NgAxw6dTo+IiPjhhx8CAwNra2uFQqFcLu/p6aFQKMXFxefn58QSOvSZ4HYmxoTMg5t7PVzMyMiIlZXV6OgoZA7z+fycnJxvvvnm2VObzPQM1ilTr9Ud04+osXEhQcH9vX1i0bVBp8cNv1ibob8RaD7Afnp2dubm5vanP/1pYWFBrVarlCrcgDEZp8WFRR5u7uWlZfSDw62NzZam5tzsnN7unlMGAyM40vE7SlsFIAcDCrp3dXXdv39/aHBQrVRh+j+Xdb4fG7ezfREcGDQ1Mck6ZQ72D+Tn5Tc1Na2urorF4p86SloCQQKfga0PQlppaWl7e3vwjkwmGx4eBm2Kjx8/GgwGFos1Ojqan5/f19cHAo0ajQbVIuPGKAxJkH8JSIK0CBDnqMFgYDKZQUFBnp6eW1tbGIZxOJyRkZH4+PjHjx97eHgMDAwIhcL9/f22trbe3l4WiwV/iIrx8RsnUHMSpJ6gea1UKltbWx8/flxZWQmNA6enp729vf38/KKiokJDQ9fX13EcX1lZqaysXFxcRNuuyXWCX8jENWQG3Lxp4PKampp6/vx5SkoKk8nEcXx9fT0iIsLDwyM8NCzAz390eMSg0wv4lw119R1t7axTJuzUOHaLz9b8uPntAoGASqU+fvy4trb2/PwcMxhwDFfKFVsbm6Ehr5ydKHs7u7gBOzk6XlpYPGNz9Lo/pynhn+ZYmp9OTL7LYFRWe/LkSX5ePu+cC4Y7juHnnLOSN2/tbF9UVVQqZHLeOXd1ZfX4+Fgmk6GOnjdHYQkESXx/amoqLCwsICBgaWkJDZnH45WUlECVlFQqFYlE29vbc3Nzp6enII1r0mLFJARDEuRnQBLkHQNmp1qtlkqlkGYGMtBVVVVOTk5xcXFNTU35+flUKrWxsbGvr6+wsDAqKgoMMplMBgdDYhqLyUHezAQJzhzUc06pVO7s7CQkJLi4uBQWFra3t+fl5SUnJ09NTTU0NDx58qSpqQnHcY1GA2PBjTRPrEK7dVzmWdUYQboM7jPsNQwGIy8vj0KhpKamdnR0FBYWJiQkDA4OjgwNOzk45mbnaFRqvU4vl8rkUpleq8MMGKY3YHqLyM2Bb1coFHQ6fW9vj8vlyuXyubk5aBrc0dEhFotxDNdptDqNtqGu/r++fzDYP6DTaLVqjUqhNOj0mOHPIizER4YRPBbmAeIPg8EAyWsMBkMulx8fH2dkZHh6eNbV1J4cHUPVo16nv7zg+3h5R0a8ZjNZep1eo1ajog7MWHBsgQTJ4/FoNNrR0ZFareZyubm5uc+ePUtMTDw9PQUj0mAwbGxsQDB1fX0dM3a/QXWQOCFUjEAS5F8CkiDvAMTZD9OXzWa/f/+eRqNBNhqO42KxuKam5sGDB//yL//i5ORUWFjI5XIlEklHR4eTk9Ps7Cz8rZ4gSvflJjpxLRGPosTtHgYC2y6NRgNxH/ir1dXV169f//73v//222+joqKOjo6kUmlzc7O1tXV5eTl+m4POQhYtZhQ9ODk52dzcZLPZKMP28PAwPz//q6+++u1vfxsREbGysqJUKldXV52dndPT02HsBsuo5UC8hYoBpFLp4uJieHh4SEgI8mx//PjR2dn56dOn4+PjSDRgamrK29u7ublZIBDIZDL8UwkLc2qVmUwPNBaNRnN2dtbS0gIZmzMzM1qtdnd3193d/fHjx6mpqSCrptfrFQpFbm5ubGzs2toaykYGzwSq2b1zoJMujuN6vV4gEDTU1Xt7eqWlpM7NflDI5Gsrq/m5edYPH8XFxHLPznEDptPpLi8vOzo6goKCxsfHb1Igif8xSII0E4j7PpEg4Z3R0dFHjx65u7sPDQ1BPZZarWaz2aOjoz09PTMzM/v7+9CQr6amJjg4eG1tDf+0Hc/dEiQayOnpaVZWlouLS21tLZ/PRzJAW1tbAwMDw8PDKysrsFU1NDS8ePGisbERJ+i3WSBB4jgOzQLd3d1zcnJYLBYq9gdR3Pb29oWFBbCAZ2ZmKBRKWloaEKSFjAJxGJh6crl8ZmYmKCgoJiYmKCjI0dExJyeHy+Uqlcr+/n4KheLs7NzU1MRms1UqVXNzs4ODw8DAADSNQk/fQMicMs8wb045EOY+OzsrLi728/MLCwtzdnb29/d///69TCabnp728/P7/vvvk5KS9vb2ZDIZj8cLCQmhUqnn5+cGY7UDkp6wkNMMokYMw46OjtLT08Nehb4Oj/Bwc3d2ooyNjOq0uv3dvdTklKePn6SlpG6sf5TL5Zubm2lpaVQqFdpxkwT5S4EkSHPAhEhMoFKp3r1795//+Z+//e1v3d3doaqJmHUG+5pQKKyurg4NDW1uboZGr0Tz8Wa44pe9fpMvuklm8O/CwoKtre2jR49evnxZW1uLWjwSP0QqlY6MjMTGxvr6+s7MzODG7cACCRIeweHhobu7+71791xcXMDeQg8FPQK1Wv3x48fc3NygoKD29nYLMUcAyMkGV7u2tpaamurn5zcxMTE5OZmcnGxjY9Pf369SqSQSSXd3t6enJ4VCSUxMfPPmTXh4OBAMRihDIh6JvujEM4HJOtLr9Xw+v6mpKSAgoKCgYGlpqamp6fnz57GxsZeXl0qlcmJiIj4+3tnZ+dWrV3l5eTk5OdAWEdqroZtDnMB3DgMhft/f329tbV1UUEjb2q6pqn7w3fdpKakcNkcpV+zv7mWkpbtQnIMDgzIzMxMSEmJjY4eGhvh8PkmQvyBIgvziIB63TQrP0SJvaWmhUqmJiYm+vr4eHh7d3d0gF4eqAtRq9fj4eHR0dEZGBoPBgBgDOgUTl8SXWBU/S5Bo852dnXVzcyspKYmNjXVxcWlpaaHT6SgWArbXxsZGampqbGxsS0uLQCAwECqXLY0gDcYW7d7e3pmZmZmZmRQKpbCwcHt7W6FQoLFDoX12dnZoaGh9fT2Xy0VEctcjwHGCQC7wOvQaW1hYgKbBy8vLbm5uxcXFdDodmjzPz88nJCQ4ODjY2NgkJibu7e1Bo13D3RV1EMdiIBQtnJ2dJScnl5eXczgcuVzO5/OjoqL8/f0PDw/VajUIrYFCqbW1taura3d3N5Q94EbJb6TNZCEWJG48ypydnTU3NycmJq6vruEYzmayigoK42JiQQlIq9acsTltre/8fHyfPHni7u7e1NTE4/GI1VAWMv1+1SAJ8ouDuKT1N8S7IYIyPj4+MTGxs7MzMTEREhLi4eExODgoEonQogUFqcbGxv39fUiBQRIzaOf6cv6unyVIdKgH8ltfXz86OoqJifnuu+9iYmJOTk6gChvH8aurq5GRkcbGxrm5ucvLS4zQusQCCRJ2TyaTWVpaOj8/z+Vyi4uLHz165OPjs7y8jBvP+5eXlzMzM93d3WNjYyip2NI2XL1Rnnd1dbW3t1ckEsHNZzKZYCzOzc1Bjye1Ws3hcFgs1v7+PofDIbZPIsZW72QXRqsJruf6+npoaAgaUOM4rlAompubobXI1dUV/IlQKGQymXt7ewwGQ6FQQL0QTig7tjSChNMMn89fWVlZXFzk8y5wAya5Fq+trCZQ48tKStlMFiRFC/iXJ0fHx8fHDAbj+vraQOjMRRLkLwKSIL84iBaeydyFfef6+vrs7Ozq6kqtVstksvHxcT8/P3d39/7+frVazWKxdnd3T05O9vb2Li4uENEiTjL52C9NkNhtjmIgEq1WK5FItre3r6+v9Xr98vJydHT0kydPkpKSzs7OJBLJ/v7+2toanU4XCATQ1s6kcP6LjuJ/ALgMuVy+t7d3dXVlMBj29vYyMzPd3d1DQkKWlpbARpmfn9/Y2Dg/P0eiJ9iNNn53CMOn8TaJRHJxcQFHFtiIy8vLCwsLu7u7xWKxVCo9OjoCCwwnNESET0DihfiXj3ybgHgUQzdZq9XyeDxovoFhmEwmm5qaysvL6+7u5vP5MpmMw+EcHBwIhULiCZK4cIhOHfMM5PNAF6PVasVisVAoVCmU0JnkjM2hxsZlZWQe04+0ag2HxV5dXlEqlOjhYl/emfT3BpIgzQqMUCYIIL40GAzAl93d3W5ubkFBQW1tbfn5+W1tbcfHxyied9N0M/N6uGntgcQX8lzBrymVyo2NjZycHGdn5+Li4srKyurq6vn5ealUeushFzN7ncDPgmhYwKVqNBoGg/Hu3Tt7e/usrKyqqqra2trBwUEQALp5Z+708v8MzCgxgyaM3qi3DjVFbW1tZWVlg4ODJycnXV1dYC7DY0KfcOfjunkNKNUWoNFoVCrV4uJiXl5eV1fX2dnZ2NhYfn5+e3s7pOneek61tIeF4zioN/z30DAcM2B6nf6MzUmMT0hPTWMyTg/29ivKyutr6wT8S+KBmziouxzD/xaQBGlWGAii4bBtQaREoVDweDzwqcIZf2hoyMPD4969e3Z2dp2dnXw+H/sJb6QlEKTBWP6o0+mur69FIhGokygUivPz8/z8/N/97nffffddVlYWjUZDIclbP8RyPF24kRS1Wq1cLpdKpTAorVYrEAja2toePHjwb//2b5GRkR8/fgQ/pCUQyU2gW02019VqtVAo1Gq1fD6/s7MzOzu7vLy8sbExJCQkJSXl8PAQVT7A6cdCxoV9GrCAf+FYCbJ/a2trhYWF5eXl9fX1oaGhbm5ug4ODKKJPhGUSJCqO0huF1wWXgmuhCDNgAv5lcmJSAjV+bGQ0Iy3d091jsH9AKpag5WOBw/m1gyTIOwBMXzgnwh5Eo9Hq6+vn5ua0Wi28ubu7GxkZ+ac//amurg5q7zBj0qAFEiRmjFFdXFyMjo6urKycnJygg3BPT8/XX38dGRlJo9GgceBN3GpT3jmA9WUy2fLy8vz8PIfD0Wq1ICq7sbHx448/UiiUyclJKBC0WAsSHaqQW1Imk9FotMHBQSaTqVQqu7u74+PjXVxcbGxskpKSdnZ2iMrdtz6vOxwOECQ4VHAc12q1Jycns7OzKysrIpFofX09Pz8/MDDQ1tY2Nja2u7tbIBDghECshRMkrAK5XA6xUjab/X5sfGP9o0Iml4olKUnJ3/7xGw8390D/gObGpmuhCMkzWeZwfu0gCfIOANMX+APDMB6PV1paGhkZOTg4CP5JuVw+NDQUGxubk5NzcHCAG01P/CestzsnSNyYuDE9PU2lUt+9e3d8fAyptiwWq6KiIjAwcGhoCDUbMfkcYpTLohY2XOr+/n58fHx9ff3FxQUcaHg8XnV1tb+/f1NTE5IOsNhc3Jvi1Nvb23l5eWVlZSB90Nzc/PTp09/97neurq7Dw8OQ/4UZrWfcMlys6OLRWQreEYvFtbW1ubm5ExMT4NV//fr1vXv3Xrx40dPTc3l5SQxh/CpcrHD/cRzncDjV1dXFhUVrK6tqpepaKPLz8f1//+f/PrT6saKsnMk4BZlZnNB0DDd7bPh/N0iCNCuIcxeWOoPBePv2rZeXV0FBwcePHyGn7vLysqamJjc3l81mw2qBPQ7yVy2QIA0GA5hZ8fHxQUFB09PT4IrUaDTT09M5OTmTk5PgQDa5VHT95mlX+ddCpVIdHBzk5uba29t3dXXJ5XJw6x0dHYEYNI/HwwmFnpZDJEQQixmUSiWNRktPT/f19e3p6VEqlRKJZHh4mEKhODk5jY6OghsZJXYSg5d3Oy4TPoN7LhAIent73dzckpKSOByOTqc7ODjIzMy0trbu6uoCzQ00llsfkKU9LLgSrVbL4XAqKiooFEp1ZZVQcGXQG2QSaUxU9HObZ5npGYzjE4NOr1GpMcOfj6ckQX4JkAT5CwMl+xmMqYO4Ma4ACxUMQaA6Ho9XVlb2/Pnz0tJSEC6B/Qhy85ASzZcG8TyOthKTn+FKIByFujGjT1AoFCsrK8HBwb6+vrOzszKZDLIKIa8VKuvNuWJ/akOE/0WhONwog643iuMAhcAv6/X6g4ODtLQ0R0fH/v5+sVgM5YB6vV4sFl9cXKBCgi8KYh4KCr+hrRAOFgqFAsfxPyemarUqhRKkU3VaHaY34Absz1LpBuyMzUlKTHz27FlbWxt0R9JoNEKhcGdnZ3d3VyQSmWFEnwfxYcGSwXEcRHPgpIgb044EAsHg4KCzs3NcXNzOzg78l0KhOD4+3t/fhzoW8/Mf0R2C33a20Bv17eDJgsceTjDwCUDzb968cXBwaGxsBEF8eH9jY2NjY4PJZKL7YJ5B/d2CJMhfGKgc22DUq7y8vJyenu7r6xsbG4O0CNi+6XR6ZWVlcHBwUVHRwcEBSqBHq8hs6SomjEhc2wZjQjxUcczNzRUXF2dnZw8ODkLdFcRLNjc3o6Oj/f39x8fHUcQUfYj5fafYjbI2kwGicen1eg6H09vbOzAwcHBwAFsVJE8xmcz09HRnZ+fW1laRSIQypHCjTWaeEZk8HZNILXo0iDy0Gi394LC0pDQ2Oqanu4d3ztWqNTqNFjNg62vrBXn5r0JCmpubQXIFSZIibes733PR5IHLgyqa3t5eOHihIwKDwSgsLHR1dU1JSdnd3UVuYVh9qKOT+QkSIzh18BsEqTdWo2IYdnp6WlNTk5qaWl9fDzsA+F1WVlaio6N9fHxqamogOxoniPhDKRF8lyU8r//dIAnylwSKFALbgcBKXV1dWFiYl5eXr6/vwMAAuH2kUmlVVRWFQikoKGCxWMS1hIwbDMPMo1hGJLNbCRLHcbVavbS0lJSU5OTk9OzZMy8vr5mZGRjs8vJybGxsSEhIb2+vVCpFGRDoBzMM4eaIiN+LXho+zSLGMGx3d/fNmzcgzlBRUQERXxzHj4+Pi4uLPTw8KisroVc70eI06aj3pcdiAhOLHxnr8M721lZleYWPl7fNk6e+3j4dbe1i0TVuwHhcXnZmVoCff2NDIzwm3OjwINqjd7vhmgzw6OiovLw8Li7Ozc0tLCzsw4cPkJtzfn7+9u1bPz8/KpUKnW30RokfNC7zeF9+agjYT/gwYFxKpZJOp0MY28HBwcHBoaSkBEQMTk5OEhMTQdSQz+fjOA6HNvhwmHgwCe9kZf29gSTIXxKIIGEeX11d1dTUBAYGJiUlJScn29vbh4aGrq2tSSSSpaWl3Nzc3Nzcg4MDjKCYjD7KzMde9KVE2wgtchDmTkxMTE5OXltbGx0ddXFxyczMhJhce3t7YGDg6OioXC43OTX/1Ld86XFhBGMLZS0CiyBLXa/Xs1isgoICNze3srKy169fv3jxoqioCFpPv3//3snJqampSSKRIAkk3Firan6CJO62yMuKDjTIaczn83Nzcl4Fh0yMv9/a2AwJCg70D+Cdc5VyxejwyOvwiJam5iuBACf4zInfQtzEzQwT+tdoNFKptKyszMnJKTExEUz5oKCg9fV1nU63tLT0+vXrioqK/f199DiIRpv5r//mcPS3FWUBsTGZzIqKirCwsNHR0cXFxdevXwcGBoKyQVlZWXR09OzsLI/HQ35UFLIhTgP0LXc91v/NIAnyFwZKatBqtYeHh0FBQSUlJYeHh/v7+7W1tVFRUe3t7Twej8FgHBwcoJ5QtyZ2mn+dI/+VCUFeXV2BEmxzczPUz2VkZKSkpIhEIoVCsb+/v7i4CK1ZDcZCAoip6G+o35mH+DGjg464p4AjEZkaarW6p6cnOTm5tbWVzWYvLS1RqdTo6GgIBrPZ7K2tLRCFBy5BZrHWCHP6wIlWIwyNaETCtV1fX6+vr8fFxuZm5wgFVziGF+Tlh70KPT1hSMWS/d092ta26EqInLFEVzP6LmIwzJwgsqNer5fJZNCisqysbGlpicFgdHd329nZDQ4OSqXS8/Pz1dVVDoeDzHriEIhh2jsETBUTgsRxXKvVrq6uJiYmxsTEiEQipVJZWloaFRXFYrGkUunh4eHCwgIEwvFPzUccxxUKhVKp/ERGgMSXBEmQfxMwQoUD+hntzjQaLScnZ2trS6/XQzm2r6+vo6NjaGhoXFzc5OQk2qd0xp7mJsxhfgvSQMhgRO5WaPLg4eGRlZUFC9jDw8PKyioxMTEqKiorK2txcVEsFmOfhhtvpXmzESRmFMBDz4X4EsMwuVze1NTU3Nx8dXWFYRifz8/Ozv7mm28iIiISEhIKCwshsgV7HHLiAcy5BWOEmBa6dcSXBqOynVAoXF5eDg4KCg4MWltdOzqkBwcGfXPvj+GhYTFR0fFx1JGhYT7vwmBMika+WexTu/9OLDC9US8NBisWi7u7u9+9e3d+fg4CFDMzM998842Li0tKSkp2dvbq6iqwyM1bYf6LNwE6kCELkujVVygUU1NT4eHhvr6+Kysr29vbVCr16dOnERERERERSUlJ4+PjqBE6MeyNfeoDv6sn9XcFkiD/JiC3GyxOtONcXV3JZDKJRLKysiIUCqGVbnZ2NoVCcXV19fLy+uabbyIjI1E2Gvqcux0O2mXQO9A2SKlULi8vR0REeHt7FxQUxMfHP3nyxMrKysXFxdbW9v79++Hh4dvb28TPuYvLNwXRfCSG2aRSKdz2vb09pOzT39/v4+Pj4ODg7e39+PFja2vr/Px8FouFbGLiR5lzgMRvhJ//nIyj1cK5CiR8IYWVy+UmJiTaPnuelpKal5P77KnNV//xn3a2L5ydKI9+fOjp7rGytIzdBuLX3eHjA/4QCoVisfj09JTH46lUKoPBcHx8XFlZ6eDgYGdnZ2tr++DBg9TU1MPDQ3SCsZApB0DzhGjl4zgukUguLy91Oh2LxSotLXV0dExJSQEn/x//+Ec7OzsbG5uvv/7a19d3e3sbKSEQ55tFDfPvASRB/k0ger2QhcHlctfX12k0msFggLw7Lpfb0NAQEhKSmZk5Nzc3OTkZHh4eEBAwNTUFCSB6y+iOhLZLuB6BQLC6ukqn02UyGZ/P7+npoVKpr169sre39/f3b2lpWVxcXF9fz8nJ+fbbb8fHxy1hCEToCb2ZcOMZXK1W83g88J1KpVLQVRcIBMnJyX5+foODgx8+fGhubo6MjPTy8pqfn8cJRAucZObMo5sECUUdCoUCLgYcwufn5ziO63S68bGxrIzMsFeh7q5uQQGBBXn5i/MLK0vLxYVF1g8ftb9rUyqUnyFI/O4eIqTjMhiMra0tUDBA3sWuri4XF5e8vLz5+fn3799nZWV5eXlB2NsCnY1EgkR5CQqF4uDg4ODgQCKRSKXSpaWl9PT08PBwT09PBweH2NhYUGuCnncLCwuXl5fgtzBnwJuECUiC/JtA9Jzo9XqY97m5uYmJiZGRkTU1NSBzBQ2tWltb19fXwX3U29sbFRVVWlqK9rW7HgqOEwhSp9MtLCxAF9bg4OD8/HwGgyEUCjc3N5ubm318fIqKijgcDpgyHR0dv//974eHh/FPiyPvHChAhThga2sLLGAqlZqRkbG8vAxJ81dXVx0dHd3d3SKRCLbpzs5OKyur3t5enKAmozNCb0ZNg5sECTYTeOFWV1eLioqoVCqVSgUt+POzc/rBYUdbu6+3T1ZG5s42TSaR4hi+vLhk++x5W+s7zQ3ZWPMM5GdxcXHR1taWkJAQExMTHR3d2Nh4enoKt316erqqquro6AgM6MnJSRsbm+bmZlAuxC3A+0IEkSDh8g4PD8vKypKTk0NDQ1NSUnohau33AAAez0lEQVR7e/f3909OTsbGxlJSUuLi4oaGhkCTuampyc3NbXx8nMPhkAR55yAJ8m8CyinHcVwsFo+NjYGUTEpKiqur6+PHj/f29nAc1+l0KpUK6tBxHBcIBNXV1cnJyaOjoxZoQapUqs3NzczMTFdX14SEBPA3vn//HpJU2Wx2UlJSZmbmyckJJIbU19e7uLisrq7itzlp7xAGQncRjUbDZDILCgpcXFxcXFwoFMr9+/fDwsKmp6cheopEonEcv7y8rKys9PX1nZubw40Uiz4TwTzP6yZB4kaj9uDgIC8vz9HR0d3d3d7e/uHDh8HBwQvz82ql6vKCX1RQmJ2Ztby4pFaqOGxOW+s7Hy/vyfcTep2pJB76ojucgWq1emRkxNvb28PDIyUlxdbW1srK6s2bN6enpxKJRK/Xy+VyGDv0RvXx8RkaGkItR+587RBhQpBCobC2ttbZ2fnVq1d+fn7W1tY2NjYZGRlHR0c6na6vry8yMhJUjc7PzwsKCuLi4qDdGHgLSIK8Q5AE+TeBuAUfHh76+vq6uLgsLi6en583NjYGBgaOjIyAHjSEiFQq1fn5+fv37729vbOysvh8PrEQ7c6dRbCwLy8vqVRqbGzs5ubm8fFxRUVFVFRUY2Pjzs6ORCI5Ozurqqry8/MrLCwcHBzMzs5+/fp1T0+PQCBAvlkLIUiMIJYmlUqLi4sDAwMXFxcZDMb+/v7g4KCDg8Pz58+7u7thCzYYDEKh8OjoqKKiIjQ0tL6+ns/no5JWRFFmNrxMCBKl1Go0mrdv30ZERIyPj5+enm5ubhYVFVEoFA939872jssLfl9Pb0RYeFxMbHdnV252TkRYeFVFJZvJIma1oIFgn8bMzI+Dg4OYmJiSkpKVlRU+n7+8vJycnPzs2bOYmJjZ2VnwVcjl8ouLi9bWVh8fn4qKChaLBdY8bjFTDkAkSJlMNjY2lpqaWl5eTqPRzs/Px8fHg4KCHj16lJycfHh4OD8///r161evXg0ODlZWVkZGRtbV1SH/KvEoZjlHz78fkAT587i5d2DGtDQkII7j+Orq6g8//GBjY8Nms/V6/dDQUExMTGZmZk5OTnd3N4/HUygUa2tr6enpPj4+kPmJ353KJfGLTBIy2Wy2lZVVVFQU5BmNjIwkJSXFx8cnJSW1traurq4uLy8XFRU9e/bM1dU1MjISREotwbmKMm/hJVwSvBSJRBEREa6urihFXigUJiUl/eY3v3Fxcdne3tZqtRcXF+3t7Y6Ojvb29g0NDQwGw2zX/BkzDjO6dv/8+3oDjuEalVqr1oSGvHJ1duGwOTiGG3T61eWVtJTUP/z7H1xdXbe3t7lc7ps3bx48eODo6JiQkNDS0gItVky8f78ITOaw4SeAftlgMKAGYTD9FhYWXFxcBgcHJRIJjuNqtfri4oJKpT58+DA0NHR3dxfDsI8fP4aHh7u6ur558+bo6AjOneYXNyA+I6J3AY2FGPYWiUR1dXURERGTk5NyuRzHcaVS+eHDh7S0NFtb2+Tk5K2trdbWVtDCjYiIGB4e5vF4aIe580Pz3zlIgvx5oAVvUnyGG3c32LwYDIanp+fTp0+zs7NhSbx8+fLVq1ehoaEBAQGZmZnv37//+PFjfX19dXX1/v6+zthvz5wDMXGpoevHCCJYQqEwPj7e0dExLy+vtLQ0ODiYQqH4+vomJiYGBARERUVNTk7Oz883Nja+e/duYmLi8vISEkFxM3q6DIQCeRiU/lMBOSJwHJfL5ZmZmTY2NuBTVSgUbDY7PT3d1tY2KCgoMzMTWlK/f/8+Jyenrq7u9PTUPIFhE7pCg0K/gExGVAuEGzCD3qCUK5ITk549tRkdHlHI5BqVenZ6Ji4m1sPdw9PTMyMjg8/nHx0d1dTU1NbWQq8uZGzdCUEiOkRxNSJoNFpoaGhqaurOzg4ihv39/cTERCsrq9zcXIFAsLu7W15e3tDQsLe3B8LF8GlmS5sizi6DsbrG5HCD1hScz5RK5fDwcERERE5ODpPJhD8ECb20tLQffvihr6/v7Oysq6urqqrq/fv35+fnxKIvM3M/CROQBPnzQJMecv0RtFqtSCSi0Wibm5scDufs7KytrY1KpX777bd/+tOfvvrqKwcHh7q6utHR0bi4OCsrq5SUFFjYGIYhXXJzjgIRCf6prphYLBaJRCcnJzs7O3t7e+fn5x8/foyLi/v222+/+uqrf/3Xf71//35RUdHy8nJ+fr6NjU1WVtbu7i6yz4gDMc8+hd8gSJygwkXciK+urra2tmg02unpaWdnp6en56tXr/r6+rq7uysqKqhUamdnZ0dHx/Pnz4eGhgyEVFXcXB5vtOdiP+HCReq+8JJxwlhZWt7b2RXwL0eGhgP8/F+HR8xOz4yNjObl5IYEBQ8NDoJFsrKyAok8sCNrNBpktH1pgrwJNDHQaQzDMCaTubKysri4uL+/v7e319DQYG9vX1tbi0IPWq12eXk5ODg4LCxsa2sLlEiJzhviDfylxvL5YRoIWuQ3CRI3+i2kUunGxsbMzMzW1tbu7m5aWtqjR49GRkYgNRfuxtLSkr+/f25u7tbWFhiXGo0GaVVCyoLZFhSJW0ES5M8DbSjEaIdOp7u4uGhsbHRzc3vx4kVoaGh/fz+Xy724uFheXh4cHIyPj8/MzGQwGGKxeHJyMiIiIiUlZX5+XqFQYAQJNxNb5wutB7RJIT7T6/WI4WQyWVdXV3Bw8NOnT/39/RsbGzkcDovF2tra6urqgsyCvb09ECXPyMjIyMhYW1tDqutEq9ps6Z03iQTuHrJlNRrN4eFhUVHRixcvbGxsMjMzP3z40N7eTqFQHj58+PLlS39//9HRUZlMNj4+/u233/b29iKKNafX7lZ7zsRSgdEJhcKFhYXEhISXL+w83NwryspXlpZHh0dcnV2sHz6yfvgoJSl5aGBQLpNNTEw4OTktLy+b2CImtp2ZCRKdAHAcV6vVKysr8fHx//Vf/3X//n03N7fKysrJycmAgABnZ+fGxsazszN4HFwut7q6mkql9vX1XV9fo9L7LzGKv2qk8PKmi1WlUtFotOrqakdHxwcPHjg7O9fU1NTV1Xl6enp7e4MSEDzW4+Pjt2/fJiYmQqd0ExEAkx9I3AlIgvx5EFcjbiRILpc7MDAQFRVVWFhYUFAQFhZGoVBqamo+fvwok8mOj4+zsrISEhK4XC6O4z09PX5+fmVlZcfHx5CtgxPEAb7QnmUyBMwo7UEUTgOan5ycfP36dV5eXlFRUUpKCoVCycjIgKjP5uZmXFxcQEAAg8HQ6/UfPnwIDQ0tKytjMBjo+olF9Oasf0BDIxI/7KoqlYrP5+fl5cXGxlZVVWVnZ/v4+Pj5+VVXVw8MDDQ3N9fV1Y2Pj0O/qtHR0YcPH/b09Jh8rHmiqsRt0UBwDqNbCvdZLpe/e/cuNDQ0KTGxqqIyLSXV1dklMT6ht7tncX6ho629t7tnb2dXo1LrtNrh4WE7O7sPHz4gfgXbixiA/NIEefN3iEbkwcFBVFRUampqQ0NDbW1tdHT006dP4+Li6uvrw8PDbWxsoALKYDBsbGykp6dTqdTl5WUoAIXhoAQWM7siTQ6FNy3I9fX1jIyM2NjYgoKCioqKuLg4Ozs7f39/WFnQxhliK2tra0lJSXl5ecvLy7AtEPcZ/NPqahJ3ApIgPwcDoQGpgRCrU6lUs7OzoIJBp9PFYvH09HRISMiPP/4YGBi4t7d3enqamppqa2tbV1fX0tISHR2dmpq6sLCAdig9obzpZ3eWvx3EQzcxj0Auly8tLRUWFsbHx6+srEgkks3NzfT09O+//z4uLu7s7Gx3dzcsLOzHH38sLCzs7e3NzMyMjo5eXV0FQw35mojtvcy/VRk+dbdqNBqRSLS2tubt7V1eXi6Xy8VicVtb29OnT+3t7fv7+0EAE8dxhUJBo9Hy8vJABRt9GsqNNANM5hhqO4VuKY7jWq324OAAmjy8Hx/XarSsU+abouLHj6x9vX1oW9salRoaQOIGbH1tLTc3Nyoq6uDggHh/0AT7EtTymWmMvh1t9xKJZGxsjEKhNDU1QTHD+vp6Wlqag4NDRkZGSUlJdHS0p6dnfHx8eXl5enp6SEhIXV0dmI8GY+TP8Kl4t8FcMUiTEwa6mbhxQtbX11tZWRUVFfH5fLAmMzIyHB0dg4KCYmJiPD09/fz8UlNTodFVREQEtBqFWwRuVdJqtByQBPk5GAiJJ8TNRa/X9/T0BAUFdXR0cLlcDMP4fH5fX9+9e/d+//vfl5eXc7ncxsbGp0+fPn369PHjx4mJifv7+9BuF1lyZsssIA7H5IgqFAqbmpqSkpLKysrYbDaO4wqFYnl5+fnz5/fu3WtpaTk7OysuLn758uWjR49sbGzCw8MnJiagIo0ItE2Y08VKvIHoruI4Dlo58ICGh4fhTZlMlp+f/5vf/ObFixcrKyvwVwwGIzs7Ozw8fGBgQCKRmN8cIQ4Hvh1FoSDYBi91Ot3c3FxsbGxYWNjB/j6O4Xqtjsk4DQ4M+u1v/jUtJZXDYuMGTKlQcs/OS0tKo6Oje3p6QMXpZkMJww2YYWgQ/sRx3GAwsNnszs5OZ2fnvr4++B1IIU5PT3/w4EFhYeHy8nJ6erq1tfUf/vAHe3v7jIyMnZ0dA8HkxW6EUc38yIisjM5nMpkMx/Hq6urvv/++ra0N3djr6+v8/HwrK6uCgoLy8vJXr179+7//+7179xwdHQsKCk5PT9GHWIhgCAkEkiA/B5OzKm7ctnAcHxgY8PX1LSgoAIJkMpllZWUBAQE2NjZubm40Gm1nZ6e6ujo+Pj43N3dmZgYWD4AYdDTndkxsDATvCIXC1tbW6OjoqKgo0MYTiURDQ0PR0dHfffedm5sbnU7f2tpqbGxMSEhISEjo7e0FkTacUFMBWzDs42YjGKLyOP5pZEin011dXY2Ojj579qyurg6cVxwOp6io6Lvvvnv48GFnZyf0HpmZmaFSqdCWFmVg3TlBYgS5HPRyfn4+MDDQ1dX1w+wHjUqtUii3N7eSEhL/7be/ozg6LS8uGXR63jl3bvZDRno6OPNxgvVmZoIk3sCbFp5UKh0bG3v06FFzc7PBmASOYdji4qKTk1NUVNTU1BSkSefl5fX19dFoNCRMinBXBEm8hzD5Tfq61NTUgMSBUChEj29pacnHx8fb23tgYGBiYuLt27dFRUXv3r2DrD2cwLLmGQWJvxAkQX4OBmNaIxJENhgdiYeHh7m5uU5OTpWVlUNDQ6WlpZGRkaAn5+Li0tfXJxQK5XI5k8kUCASQEQMpObpPezCZrPMvNAqcUKSFG+NekFBwcnLS0NDw4sWL7OzswcHBhoaGqKiotra24uLi58+fQ06BSqU6OzvjcrngELuZo4/jOLpLuFl2K3RkMRCsfIMxn0Wj0RwfH/v7+7u5uTU3N4+NjeXm5hYUFLx58yYlJSUrK2tlZUUul+/s7MzMzJydnRFjWndLkLBFEgW4gTWZTGZmZqadnV3k69ddHZ1dHZ1JCYl1NbV1NbWhIa+qKirPOWeSazFta3tqcgrqHX9qamE38CWGAxMMZXLp9XoobQQ/yvr6+suXL8Fdf319bTAYFAqFXC7v6+vz9/ePi4uDbogw34gLEK0aYgIzZkYXK3pMxGixVCqFoWEYNj8/7+fn5+Dg0NraCtcPTxAyp8rKyoRCIewGSqUSyRYSPeokLAckQX4OKOETx3GZTHZ0dAQ9vmHFLiwsuLu7f/fddz/++KO9vT1MfRaLlZmZWVZWtre3B7n1oNKCGzsuwV6MVgIxePaFRkHcBDEMU6vVdDodDEHMKBQZHh5ubW398OFDV1fX5OTk/f19Go2WnJxcVla2s7MDgTFi6rnu016P5rcg0VegtHg+n89kMtEJ5vr6urOzEzIJ7ezs3N3dh4aGBALB7OxsaGhoS0sLxLSQH9JCCJJYYXJ8fMzj8SC/RqvVLi0tlZSU2D63fWj1o53tC39fv6WFxXPOWXVlVXwcdWlhEVyvOu0nPlUz19oCYCzowKRSqS4vL+fm5hobGycmJkQikVQqraurc3R0DAsLGxsbQ5lrcrk8KSnJzs6OyWSa0B4aETplEme12WyvmxYkm82emZnp7OxcWFg4OzsDmnd1dXVxcRkfHwfdA41Gw2AwQkJCcnJyWCwWUWPdbGdKEv8DkAT5ORDtrampKQqFEhUVRafToQWPRCL5+PFjW1tbY2Pj2NjY2dkZhmF7e3tZWVkFBQVHR0eQbWGyotA6B/pEtosZjEgcx1Uq1cbGRlBQUEZGBo/HQ9sxnU4fGBioqanp6emBLkLr6+spKSnl5eXHx8cmFR0mI9IT6r7NlqRjIGT64Th+dXWVn58fHh4O8rZwPdAfsb6+vrW1dX5+nsvlymSyycnJuLi4jo4OkGBFRrCFECRqf8bn86lUalhY2Pr6OqjgisViPp8/NDhUV1Pb0da+t7OrlCsuuLza6pqsjMzV5RUcw9VKFY79dwOTOxkL/qlBL5PJNjY2Kisr7ezsrK2tra2tU1NTmUzmxcVFYWHh06dPPTw8hoeHRSKRRCK5uLhITk4ODAxkMpk4wY9KDM5hn4afcfMSJPpGeGQsFisnJwdqhx4+fJiTk3N4eCgSiaanp93d3e3s7Pr7+wUCAXRCDg8Phx5qEJE1fJriQFqQFgiSID8HzBjTEolEpaWl//Ef//H111/HxcVxuVy9UQjq8vISFoBer5fL5WNjYz4+Pu/evQMVcuKMv6vdCic0fhKLxf39/VZWVl9//XV2djYk5sAYJRIJn88HEUgcxzs6Ol6+fDk6Ogp60HfFHDdh4mqDrZPNZgcGBv7zP/+zs7Pz9PQ0WCRwBLm6uoK2gjqdbmtrKzIyMiMjY3193ULiPTf9hGq1WqPR0Gg0CoXyD//wD+Hh4XQ6XW+sjr++vgaml8lker1+bGwsLCysqamJw+GYMy/6M8NB7AWP5uTkhEqlOjk5FRUVgYqvvb39u3fvMAyj0+lFRUVOTk6Ojo5ZWVn19fUJCQlQUgwVOLfeqDuEniBDgeP49fV1V1eXh4dHQkJCXV1deHi4nZ1deXk5/Nfg4KCjo6Ojo2NcXFxDQ0N2dnZQUFBPTw+yKXELkF8m8XmQBPk5IOfb3NxcSkpKfn5+VFSUnZ1dZmbm7u4ubqy6gwXDZrM7OjqSkpKoVCqNRsOMvdrvcLdCQARJp9MrKipAD/bFixfFxcV0Oh3pceM4Dt2eR0dHY2JiEhMTT05OMEKg9M53KPzTmk60W62urkL7ETc3t4CAgIGBAcT0cP1KpXJvb6+4uNjX13dsbEytVhPbd9whTAgSolY8Hq+rqysuLs7b29vZ2TkyMnJpaclgjLnCwOVy+cTEREpKSkJCAmjJok8z/5QjHlmInhIcxxcWFl68eBETE8NkMrVaLVTWBgUFnZycgOt1fHw8PDzcycnp1atXoFMhEoluMoclECROaA6q0WhOT09TUlKKi4uPj491Ot3+/j4EVi8uLnQ6nVgs/vDhQ2RkpLe3d0BAAPS/Ozo6gomnJ6iOkLBYkAT5MwA36fj4+Nu3b4+PjxkMRllZ2cOHD2NiYqCQGeqv1Wr11NSUt7d3XFzc0dERsCOx/OvO1zZsWAcHB5WVlbOzs7u7uwUFBY8ePcrOzt7c3NRqtUqlEtIidnZ2wsPDMzIyWCwWlGZbIEFiBM08hUIxNzdXXV09OTk5Nzfn5eXl5eVVVlbG4/GgaBXHcYlEUlVVFRoaCtyJW0zUx4QgYcek0+l1dXX9/f0fP35saGh4/PhxXFzc3t6eTCZDOZ9CoTAzM9PT03Nqaop4xLkTgjQhZngTjo9QCNjc3Hx9fa1Wq8VicVNTk7Oz887ODjxBjUbDYrFmZ2d7enpWV1evrq5AjtEEFkKQKLCqVqtPT08LCwunp6dhmQgEgry8vOjo6Pn5+cvLS5iZl5eX8/PzAwMDHz58ANsRjcIShkPi8yAJ8nPAjJmfXC53Z2cHKOTk5KSiosLNzS0yMhJ8X1KplM/n8/l8Go22vb0NESODseQRlXPc7UAwY0vng4MDkUikUqlYLFZubq6tra2Pj8/a2ppOp5NKpQKBQCKR0Gi0k5MTpAZggQSJjiZg4l9cXHA4HEisHxoagq57VVVVfD5fLpdLpVKxWMzhcGg0mlgsBivNQrxbN12sBoNBJBLR6XTwmnK53Pr6eicnp7CwsJGRkevra41GA5mQdDqdTqfDfENz7KYRabZRmHwpTBuZTMZkMs/PzyHwptVqOzo6HBwcNjY24PjC5/PFYrFYLBYIBFBGRZQyIMISph9K3MMwTC6XQ8YNZO2JxeLOzs7U1NShoSEWi6XVamUymcgImUxGTE7GLaZNOonPgCTInwdmbLOAOsuz2ezs7Gw7O7u0tLSZmZn29vaamho4IKM/QRrT5hcEuAliTAjJPeM4zmazExMTXV1dQQGgra2tpKSExWIZCP0pISPJ0ggSalQQzwFDQFxHoVD09/eHh4dTKJTKysr+/v7i4uLV1VU4v6NdCWVO3i1MCJJ4nEKzCMxfW1tbX1/ftra27u7umpoa6KqGG9X+iHaJ+QkSfTUx4wkN0GAsBIIs7uHhYS8vr62tLfCNFxYWDgwMQDox9BVHf2WBBElcGibHLJVKNTo6CppTJycne3t79fX1w8PDoL0Ov0NUA7CE4ZD4PEiC/BzQPoWmMixUKLN78+bN48ePnZycgoODi4uLr66uYBlAUj4UNpnUQtzJksCM3khiZjmGYWq1Ggoc29vbobmjl5dXWlra+fk5unh05kW59ea/fhMgCxLZWwZjlyt0lFEoFKenp3FxcS9evHBycnJ1dZ2cnFQqlVCNZ1EV2WhWoHFhxgpCGBrcdh6PV11dHRAQQKFQHBwcqFTq0dGR/lMBoztM0jGxGhFu/pdOpxsfH/f3919aWpqZmYmMjHRwcGhvb8eMRrDBWGiLEXKMLed8RpxsROV0HMelUuno6OibN2+amppGR0dLSkp8fX27urogrRplepucHu50NCR+BiRB/hUwGAyg6AEl/8vLyz4+Pvfu3auoqADHFzJuIBHRQma/yc6CERxxOI5rtVoej/f69ev79+/Hx8fv7+8DhRC3JAskyFtpgPivWCweHh5+8uTJ8+fP+/v7iZuUJeyzCCaj0BuVm1DXLfgX8lqLioru37/v6em5vLyM/bTJaH6CNDkFYoTQO/EHUM6bmJjw8fEB0TUPD4+6ujo+n/9TDxQjHIYsBDeZW2/UmF1YWCgtLY2JiQkMDAwMDCwuLj45OUG/edOfZFFTkcRNkAT51wH8PyqV6vr6emBgwMvLKyQkZH19HTeKn6G6QBMBqjsEcZdEaxuVNsrl8sXFRT8/Pz8/v4mJCRgCEqXDbpgFd76kEZEgFjcYiz2QyWIwGK6urkpKSuzt7QsKCsDHZQZNhv8BTFiBaGcgcXwcx2Uy2fDw8OvXrz08PFpaWsBdTDTR7pYgb34p1NgQV4TBmKM7OTlpY2MDwe/Kyko6nf5Tl235BKk3dsXBcVwqlU5NTUVGRn777bc//PBDdnb21tYW7BiYsWCMJMhfF0iC/OtgMEZTQKEtLS1tc3NTo9FA3h3qKIRZTNId/mnWHDIE4TqVSiWbze7u7o6Pj5+dnVUoFDpjT0QEZHihD7nbcSGCRKIEmDGBkxiPFAgEiYmJBQUFZ2dnIG9mYhZbCEx8kkTvIrpgvV4vFotLSkpCQkJGRkbEYjF4KTCCl+9uCRL/VEAcM/pRkIKawdikU6/XLy0teXp6Pnr0qLW1VSQSAWv+qgkSLk+pVK6trQUHB3/zzTcRERH7+/vESqSb/lWcJEiLB0mQfx2Ip0UGg4EKIXBCZ0R4aTlTH12JwdhZHlELKLSxWCwYiIGgboocfSbaePhdD+3W84fJleM4LpVKNzc3GQwGpFaZJBBaDkxYAVGFgdCgW6/Xy+VyNpu9s7MDtSs/9ed3S5DE4C4ie+LvwFhOT0+7urrGxsaEQiHktf16CZI4D0HGYWJiorW1FVrCoagELCWSIH91IAnyrwaKCSE6JGalExf2HV/op8CMVheYuShbElJ19MZuwyZ7tOV4VhE+wwTIvsdxXKfTKRQKsOzhYd31hd+OW4mByC4Go7wOvHOriWlpBAnXSUzXhOMjjuOQJwXiU+ji9TdajvxaCBKpwqIhX19fX11dgXC5ySPDbhPJu8OBkPhZkARJggQJEiRI3AKSIEmQIEGCBIlbQBIkCRIkSJAgcQtIgiRBggQJEiRuAUmQJEiQIEGCxC0gCZIECRIkSJC4BSRBkiBBggQJEreAJEgSJEiQIEHiFpAESYIECRIkSNwCkiBJkCBBggSJW0ASJAkSJEiQIHELSIIkQYIECRIkbgFJkCRIkCBBgsQtIAmSBAkSJEiQuAUkQZIgQYIECRK3gCRIEiRIkCBB4haQBEmCBAkSJEjcApIgSZAgQYIEiVtAEiQJEiRIkCBxC0iCJEGCBAkSJG4BSZAkSJAgQYLELSAJkgQJEiRIkLgFJEGSIEGCBAkSt+D/AyQeUAAVCPRRAAAAAElFTkSuQmCC
图癌症相关的蛋白-蛋白相互作用领域发表论文数逐年上升。使用PubMed 数据库对下列关键词进行检索:protein–protein interaction, tumor, cancer, and inflammation。
尽管PPI 相互作用是治疗发展的难点,但其代表了一个高度有潜力的靶点。PPI在癌症中形成信号节点和枢纽,沿着分子网络传输病理生理线索,实现一个集成的生物输出,促进肿瘤发生、进展、侵袭和/或转移。因此,通过对癌症起着关键作用的PPI 通路的干扰,成为一个神奇而有效的削弱癌症信号传输的策略。由于近些年对癌症生物学的认识获得显著的提高,靶向PPI 作为抗癌手段的研究热情也大幅提升。
2.靶向PPI 的挑战和当前的策略
(1)发现PPI 调节物的挑战
靶向PPI 存在一系列挑战,主要包括:(i) PPI 相互作用区域大, (ii) 缺少有深度的结合口袋,(iii) 结合位点的不连续性和 (iv) 普遍缺乏天然配体。
(2)当前发现PPI 调节物的方法
基于结构的设计 结构研究鉴定了PPI 关键的肽段和氨基酸。这一信息与功能分析结果相结合,为蛋白-蛋白相互作用调节物(PPIMs)的合理设计提供了基础。模拟结合肽段的结构理所当然的成为了一个广泛使用的PPIMs 设计的方法。这一方法的应
用成功获得了BCL2、XIAP、NOTCH 和MDM2 的强效抑制剂。一般以结构为基础的方法包括分子模拟计算和具备展示技术的肽工程如噬菌体展示、基于α-螺旋和β-片层分子支架的小分子设计以及具有一个稳定α-螺旋结构的构象限制装订肽的合成。
小分子筛选方法 与基于结构而进行的设计不同,这种筛选方法能够发现没有结构信息或者信息非常有限的小分子PPIMs。包括高通量筛选方法在内的多种方法用于靶向PPI 作用热点的化合物的确定。高通量筛选方法还可用于PPI 作用中的诱导性口
袋以及变构调节剂的揭示。PPI 作用中最常用的高通量筛选技术包括荧光偏振和荧光共振能量转移。除了生物化学和细胞水平的高通量筛选方法外,基于片断的筛选是另外一种常见的发现PPIMs 的方法。一般有两种方法用于三维化合物库的计算机筛选:基于配体(也被称为基于药效团)的方法和基于结构的虚拟筛选。
3.临床PPI 靶向在癌症中的验证
成千上万个化合物已经作为不同PPIs 潜在的抑制剂进行测试,结果令人鼓舞。糖蛋白IIb/IIIa 的抑制剂Titrobifan 和CCR5–gp120 相互作用的抑制剂Maraviroc 目前已经分别作为心血管和抗HIV 的药物上市。这些药物表明了PPI 靶向治疗多种疾病的可行性。另外有数个抗癌化合物已经进入了临床研究,突出了PPI 靶向方式治疗癌症的潜力。
(1)MDM2-p53 相互作用抑制剂:PPI 靶向的突破
几个MDM2-p53 的PPI 抑制剂已经进入了临床试验。例如,通过化合物库筛选获得的系列的顺式-咪唑啉类似物,这一类化合物命名为Nutlins。Nutlins 在MDM2的结合口袋中与p53 的Phe19、Trp23 和Leu26 氨基酸具有相同的结合模式。对Nutlin-3 进一步化学优化得到了RG7112,RG7112 作为第一个MDM2 抑制剂于2007年进入了临床研究,用于晚期实体瘤的治疗。另外一个MDM2-p53 的PPI 抑制剂RO5503781 目前正在进行I 期临床试验,用于晚期恶性肿瘤的治疗。
(2)模拟Smac 肽段的结构得到新的XIAP 拮抗剂
一个常用的确定PPIM 化合物的方法就是模拟结合肽段的结构。基于结构的设计,结合靶向化合物库的生成,得到了GDC-0152,这是第一个进入临床的Smac 类似物,用于局部晚期或者转移性恶性肿瘤患者的治疗。另外一个进入临床I 期试验的Smac 类似物GDC-0917(CUDC-427),已经完成了在晚期实体瘤和淋巴瘤患者的试验。结构相关的Smac 类似物LCL161 已经进入了临床II 期试验,用于三阴性乳腺癌的治疗。其它的非肽类XIAP-Smac 抑制剂包括可以口服的衍生物AT-406和两个二价的Smac 类似物TL32711 和HGS1029,这三个抑制剂目前都在进行临床试验,用于不同种类癌症的治疗。
(3)基于片段筛选(FBS)方法发现线粒体凋亡通路的调节剂
模拟BH3 区域的小分子化合物显示出重大的治疗潜力。通过基于NMR 的FBS方法结合结构优化获得了数个BH3 类似物。例如,ABT-737 对BCL2 和BCL-xL 具有很高的结合亲和力(纳摩尔级别)。通过天然产物数据库的筛选,获得的一个口服的BH3 类似物Obatoclax(GS-01570)目前正在进行II 期临床试验,用于小细胞肺癌患者的治疗。
(4)PPIs 的变构调节:热休克蛋白90(Hsp90)抑制剂
抑制Hsp90 的同时可以关闭多条致癌通路,因此靶向Hsp90 的PPIs 用于癌症治疗成为了研究的热点。17-去甲氧基-17-烯丙基氨基格尔德霉素衍生物17-AAG 目前正处于临床I 期和II 期试验研究阶段,用于多发性骨髓瘤、淋巴瘤、IV 期胰腺癌、非小细胞肺癌和实体瘤的治疗。其它处在临床研究阶段的Hsp90 抑制剂包括IPI-504(临床II 期)、BIIB021(I 期和II 期)、PU-H71(I 期)、NVP-AUY922(II 期)、AT13387(I/II 期)和KW-247(I/II 期)。
http://ars.els-cdn.com/content/image/1-s2.0-S0165614713000783-gr3.jpg
图. 已经进入临床试验和新出现的蛋白-蛋白相互作用(PPI)抑制剂示例处于临床I–III 期的MDM2-p53、BCL2、XIAP 和Hsp90 的PPIs 抑制剂。最近发现的潜在的PPI靶点和抑制剂包括MLL1-WDR5、β-链蛋白–TCF、BCLAF1–L3MBTL3、BRD4-组蛋白H4 和14-3-3 相互作用。
4.靶向PPI 的新机遇
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尽管已经确证的PPIs 仍然是治疗发展活跃的靶点,但是抗癌药物的发现也呈现了新的概念和有希望的PPIs。例如,对癌症基因组学和PPI 介导的表观遗传机制的不断认识以及癌症特异性的致癌融合蛋白的确定,揭示了大量新的PPIs 与癌症的病理直接相关。对于各种癌症治疗后果和诱导性耐药的分析,使不可预测的PPIs 成为了能够增强治疗效果的潜在的癌症靶点。
(1)癌症基因组学
为了系统的检测癌症中PPI 网络的改变,我们进行了大规模的试验,基于来自多形性成胶质细胞瘤和其它类型肿瘤的基因组信息,建立了癌症相关的PPI 网络图谱。这些研究和预测的新的PPIs 共同揭示了PPIs 是癌症的主要驱动者,因此可以成为治疗开发潜在的靶点。
(2)调节表观遗传机制的PPIs
癌症基因组学研究不仅证实了癌症经典标志物的重要性,也揭示了与癌症密切相关的新的特征,例如表观遗传的紊乱和RNA 拼接。最近的研究显示表观遗传机制紊乱在癌症中的作用可以为PPI 靶向提供新的机遇。一个作用很强的选择性化合物UNC1215 能够有效地阻断甲基化组蛋白与L3MBTL3 甲基赖氨酸结合蛋白的相互作用。另外两个小分子JQ1 和I-BET 能够阻断乙酰化组蛋白与含有bromodomain 蛋白的结合,它们属于bromodomain 和extraterminal domain(BET)家族的泛抑制剂。其中,I-BET-151 对致癌融合蛋白诱导的白血病有较好的效果。
(3)致癌融合蛋白的PPIs 具有癌症选择性
PPIs 对许多酶的催化活性具有重要作用,同时也可以靶向此类酶,主要包括表观遗传修饰酶类。
(4)蛋白复合物中的PPIs
选择性的抑制复合物中的特定的PPI,从而达到预期的治疗效果,这具有一定的难度。另外一个挑战就是通过高通量筛选进行选择性制剂的实验验证。
(5)联合治疗中的PPIs
癌症中PPI 靶向的另外一个机遇是因治疗引起的PPIs 癌症信号网络的重新排布。PPI 的调整有望在未来基于机制的联合用药中发挥更广泛和重要的作用。
5.结语
一些最新的进展将大大加速未来靶向PPIs 的研究。对PPI 作用本质和成功的PPIMs 的理解能够为PPI 库提供合理的设计策略。能够密切反映生理条件并能解决多蛋白复合物问题的PPI 分析技术,可能缩短先导化合物的发现过程。在基因定义的模型系统中进行PPI 靶点发现和功能验证,对推动PPIMs 进入临床研究至关重要。这些研究活动由一个新的美国国立创新组织——癌症靶标发现和发展网络(CTD2)所支持(http://ocg.cancer. gov/programs/ctdd.asp)。CTD2 的目的在于通过加速包括PPIs 在内的新的潜在靶点的发现,加紧巨大数量的癌症基因组学信息与有限的治疗之间的联系。CTD2 网络关注癌症治疗发展的潜在靶点的快速识别和表征,强调有互补性和独特专长的协作成员之间的互动。这些科学的努力将显著的加速PPI 靶点范围的扩大,由此我们希望将曾经认为不能够实现的靶向应用于个性化癌症治疗和精确医学。
顶下学习了谢谢LZ 支持丁丁:)很好的材料,学习中! PPI啊,好有难度的工作! 国内做ppI的组大部分集中在p53吗? leos 发表于 2013-7-26 23:16 static/image/common/back.gif
国内做ppI的组大部分集中在p53吗?
国内做p 53和hsp90的感觉不少。 这么好的帖子,确实需要大大的关注啊,:lol 学习中.... 国外的水平就是高,总走在前面 楼主,有个问题想跟您交流一下,我做的化合物分子经过靶标筛选和验证之后是一个比较新的PPI抑制剂,但是这两个蛋白的作用模式还不清楚,只是有很多文献证明这个PPI跟肿瘤相关,我的化合物做了细胞核体内的药效,活性还可以,靶标验证方面通过一些生物的方法也证明化合物可以有效地破坏这个PPI,只是不明确药物的结合位点和作用机制,您觉得我的这个工作可以作为药物化学的文章来发表么
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