• <pre id="lvu8t"></pre>
    <table id="lvu8t"><ruby id="lvu8t"></ruby></table>
      960化工網
      疫情期間推廣專線15252491845(微信同號)
      靶向補體疾病根本病因!諾華首創補體因子B抑制劑iptacopan治療C3腎小球病(C3G)療效顯著!
      2021年12月25日 15:36   化工熱點

      關鍵字:

      腎臟(圖片來源:parashospitals.com)
      2021年11月10日訊 --諾華(Novartis)近日宣布,評估首創口服選擇性因子B抑制劑iptacopan(LNP023)治療C3腎小球?。–3G)患者的2期臨床研究(NCT03832114)在2個患者隊列中均達到了主要終點。這些數據在美國腎病學會(ASN)2021年年會上發布。
      C3G是一種極其罕見和嚴重的原發性腎小球腎炎,以補體調節失調為特征。該病在世界范圍內的年發病率為百萬分之1-2,在美國約有10000例、歐洲約有10500例、日本約有3200例、中國約有32000例。C3G通常在青少年和青年成人中被診斷出來,該病預后很差,約50%的患者在10年內發展為終末期腎?。‥SRD),50-70%的患者在腎移植術后復發。
      iptacopan是諾華生物醫學研究所發現的一種首創口服因子B抑制劑,因子B是補體系統替代途徑的關鍵絲氨酸蛋白酶。iptacopan有潛力成為第一個延緩C3G透析進展的靶向療法。在2021年10月,英國藥品和保健品監管局 (MHRA)、 英國國家衛生與臨床優化研究所(NICE)、蘇格蘭醫藥聯合會(SMC)聯合授予了iptacopan治療C3G的“Innovation Passport(創新護照)”資格。
      此次ASN年會上公布的是一項開放標簽、2個隊列、非隨機2期研究,旨在評估iptacopan對尚未進行腎移植的C3G患者(隊列A)以及已接受腎移植且隨后在移植器官中發生C3G復發的患者(隊列B)的療效、安全性、藥代動力學。研究中,除了接受背景療法外,患者還接受口服iptacopan(200mg,每天2次)治療12周。隊列A的主要終點是從基線到治療第12周蛋白尿的減少(通過UPCR 24h測量)。隊列B的主要終點是從基線到第12周腎活檢C3沉積評分(基于免疫熒光顯微鏡)的變化。研究完成后,所有患者都可以選擇在長期擴展研究(NCT03955445)中接受持續的iptacopan治療。
      最終分析顯示:(1)在隊列A患者(n=16)中,治療第12周,蛋白尿相對基線顯著減少45%(采用UPCR 24h測量,p=0.0003);(2)在隊列B患者(n=7)中,治療第12周,C3蛋白沉積相對基線顯著降低(采用腎活檢C3評分測量,p=0.0313)。(注:隊列B入組了11例患者,但只有7例患者有數據分析C3蛋白沉積的主要終點)
      此外,2個隊列在治療12周期間均表現出強烈且持續的補體替代途徑活性抑制和血清C3水平正?;?/span>。在2個隊列的匯總數據中,通過估計的腎小球濾過率(eGFR)評估,12周后腎功能保持穩定(與基線相比平均增加1.04 mL/min)。先前提交的長期擴展研究(NCT03955445)數據顯示,當時共治療了6個月的7名患者的腎功能得到了維持,這表明擴展的iptacopan治療可能延長甚至可能預防腎衰竭的發生。
      在最終分析中,iptacopan顯示出良好的安全性和耐受性,沒有疑似與iptacopan相關的嚴重不良事件。
      該項研究的首席調查員、英國紐卡斯爾大學腎病學家Edwin Wong表示:“在ASN年會上公布的數據詳細描繪了iptacopan治療C3G患者的潛力,以及治療腎移植后C3G復發患者的潛力。這些結果對C3G患者很重要,因為蛋白尿是腎臟疾病進展的關鍵風險預測因子,而C3蛋白的沉積最終會導致炎癥和腎臟損害?!?br>諾華制藥全球藥物開發負責人兼首席醫療官John Tsai表示:“C3G是一種毀滅性的疾病,患者最終可能會面臨腎透析或腎移植。由于目前沒有批準的治療方法,因此對可以延緩腎功能衰竭進展的治療方法存在著顯著未滿足的醫療需求。這些數據表明,iptacopan能夠強烈而特異地抑制C3G的關鍵驅動因素——補體替代途徑。結果還表明,iptacopan有潛力為C3G患者提供第一種靶向治療,我們正在積極招募患者參與關鍵3期appEAR-C3G研究?!?img src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAW0AAAFtCAYAAADMATsiAAAAAXNSR0IArs4c6QAAAARnQU1BAACxjwv8YQUAAAAJcEhZcwAADsMAAA7DAcdvqGQAAED8SURBVHhe7X0J/FXT+n6D5nlQUioSyXAviQahAZdCaSBDo2u6iUT8ZLpRFBkLJV0RUSlCpYHKUNGghAZpjkozaX7/v2f9f+vc0+mcs/c+5+y91977WZ/P+Ri+a3jX8679rLXf9b7vziMsRIAIEAEiEBgE8gRGUgpKBIgAESACQtLmIiACRIAIBAgBknaAlEVRiQARIAIkba4BIkAEiECAECBpB0hZFJUIEAEiQNLmGiACRIAIBAgBknaAlEVRiQARIAIkba4BIkAEiECAECBpB0hZFJUIEAEiQNLmGiACRIAIBAgBknaAlEVRiQARIAIkba4BIkAEiECAEIg0ae/evVsOHToUIHVRVCJABKKOQKRIe/Xq1fLggw/K2WefLYULF5Y8efJI3rx5pWrVqnL99dfLpEmT5PDhw1FfE5w/ESACBiMQCdI+ePCgPPLII1KwYEFF1Ol+DRs2lOXLlxusMopGBIhAlBEIPWkfOHBAWrduHSPqsmXLSq9evWTatGmyZMkSWbhwobzxxhvSuHHjWJ1y5crJN998E+V1wbkTASJgKAKhJ+177703RsatWrWSbdu2pVTFO++8I0WLFlX1K1WqJBs3bjRUbRSLCBCBqCIQatJetGiR5M+fX5Fwy5YtbV06jh8/XvLly6fadOrUKarrgvMmAkTAUARCTdodO3ZU5FukSBFHp+Y2bdqodrCBr1271lDVUSwiQASiiEBoSXvfvn1SunRpRb7XXHONI93OmDEjZlJ58cUXHbVlZSJABIiAmwiElrRxwai9RJwSLwi/ZMmSqn27du3cxJ99EwEiQAQcIRBa0h49enSMtCdPnuwIFFSGLzdI+5xzznHclg2IABEgAm4hEFrSfvXVV2Ok/e233zrGr1mzZqp9jRo1GHDjGD02IAJEwC0EIkHac+fOdYxfo0aNFGnXrFmTpO0YPTYgAkTALQRCS9pjx46NnbQnTpzoGL/atWur9vXr13fclg2IABEgAm4hEFrSRii6voh88sknHeG3Y8cOKVSokGrfpUsXR21ZmQgQASLgJgKhJW1k74M9OpPT8rvvvhsj/FGjRrmJP/smAkSACDhCILSkDRT69OkTI98pU6bYAmb//v1Sp04d1a58+fKC9K0sRIAIEAFTEAg1aSPPSMWKFRUBV6lSxTK6EWlZe/bsGSP6/v37m6InykEEiAARUAiEmrQxwQkTJsTyj5xwwgmSymd706ZN0qFDhxhhw3sEQTYsRIAIEAGTEAg9aQPsESNGHPHRAwTM4EQ9cOBAefzxxwW5RnQEJE7lDRo0kM2bN5ukJ8pCBIgAEYjGSVvrecGCBXLRRRel/QAC8miDxPfu3cvlQQSIABEwEoFInLQ18vAomT9/fux03bRpU2nevLl069ZN4DGyc+dOI5VEoYgAESACGoFIkfbs2bNlyJAhAg+RxDJz5kwZNmyYrZzbXD5EgAgQAb8QiBRp33PPPco8smvXrqPwvvnmm1X+7GSE7pdyOC4RIAJEIBEBkvb/IULS5sNBBIhAEBAgaZO0g7BOKSMRIAL/hwBJm6TNh4EIEIEAIUDSJmkHaLlSVCJABEjaJG0+BUSACAQIAZI2STtAy5WiEgEiQNImafMpIAJEIEAIkLRJ2gFarhSVCBABkjZJm08BESACAUKApE3SDtBypahEgAiQtEnafAqIABEIEAIkbZJ2gJYrRSUCRICkTdLmU0AEiECAECBpk7QDtFwpKhEgAiRtkjafAiJABAKEAEmbpB2g5UpRiQARIGmTtPkUEAEiECAESNok7QAtV4pKBIgASZukzaeACBCBACFA0iZpB2i5UlQiQARI2iRtPgVEgAgECAGSNkk7QMuVohIBIkDSJmnzKSACRCBACJC0SdoBWq4UlQgQgUiT9oYNG+TAgQNqFdx8881SsGBB2b9/f+RWxeHDh2Xt2rWRmzcnTASCiEAkSRsE1atXLzn22GOlbt26MmvWrMiS9rJly6Rly5ZSrFgxad++vaxatSqI65gyE4HIIBBJ0q5YsaLkzZtXGjduLKVKlZL8+fNLmTJlInXS3r59u9x3331SpEgRNe8mTZrIMcccI8WLF5fHHntMdu/eHZmHgBMlAkFCIDKkjdN0rVq1JE+ePHLyySfL+++/L4cOHZL169dLp06dFGGByB999NFQExbMQcOGDZPjjz9ezbdZs2by3XffqTU7Z84cueCCCxRG1atXl1GjRsnBgweDtJ4pKxEIPQKhJ+3Vq1er136cpnGqfvLJJ+XPP/88SrFRICxsXDAHgZRr1qwp48aNUxtXfAFJjxw5UqpVq6bqXXjhhfLNN9+E/kHgBIlAUBAILWnj9R6v+Xjdxym6Y8eO6lSdroSVsGCnvu666yRfvnxq43rqqaeSblzx2OzatUsefvjhGH5dunQRXNyyEAEi4C8CoSNtEC9e6/F6j5Niw4YNZfbs2Y5QDgthYeOCuUdvXJ07d7bcuBKB+uWXX6Rdu3bqTaV06dIyYMAA2bNnjyM8WZkIEIHcIRAq0v7222/V6zzIumrVquo1Pxub7MqVK48grP79+weCsPTGpU0csFPD/JNN+fzzz6VOnToK21NPPVU++OCDo0wr2fTPtkSACNhDIBSkvXHjRunatasyg8B17aGHHhKclnNVQFjnnnuuIqxTTjnFaMKaO3euNGrUKLZxvf3227Y2rkTbdjLs4MM+dOhQqVSpkrrEvOyyy2TRokW5gpn9EAEiYAOBQJM2XtOffvpp5a6H1/e2bdsKTsduFBDWa6+9Zixhwd4Mu7N223vkkUccecG89NJLtv20t27dKvfee68ULlxYChUqJN26dZPNmze7ATv7JAJEIAGBQJI2ToUffvhhzIUPr+2fffaZJ8rdtm2bUYSFjQtmG9ibsXFde+21Aju003L33Xcrwi9RooRtP+2ffvpJrrzySnXBiUAlEP/evXudDs36RIAIOEAgRtoIZf7rr7/Uz64dGKdP1Lf7oMJHGIQyffp0RbowO+CEaOfVXM/p+++/V6/leD0/7rjjZMiQIb6EnvtNWMBs/PjxylwDsw3MNzNmzHCg+qOrwu6Ni1snftpYNxMnTpQzzjhDtTvrrLPk008/Ffx/FiJABHKPQIy0QUJly5ZVv3fffdfWSHCjQ32cdNMVRN/16dNHBbWAbPFw6x9OaXjQcUpL5j8d32/v3r1V9B5ey3v27Cl4TfezgJgmTZrkOWHBjnzJJZcoDGFfhtlG51DJFg/t9oiLXCd+2ti4X3jhBSlfvrw6eSM0HiHyLESACOQWgRhpL1myJEakI0aMsDVK69atYxGGqRogoEMTAEgApF2yZEmpXLmy8hnGA64JvHbt2rJw4cKUY8N+3aJFC8EGY1KJJyzMD4S1dOnSnIsIu/G//vWv2MYFuzI2RDeKdnvExS7MJrjoteOnvWnTJrnjjjuUjAiRR44XmJRYiAARyA0CrpL2tGnTlDcHSBkXVrfffrssWLAgdiqEeWX+/PmxCzTUK1eunKqTrMAkYPJrdzLCygWpYlN48cUXY6fYq666ypVNIRnm8X7auPC166eN0HiEyGMTQ8j866+/nrO3gdwsffZCBIKJgGuk/euvvwoSM4GI8U+cuNOVCRMmxAgeZpSdO3cGE9H/lToZYWWS8hUb1OTJk2PmlzPPPFP9tx8bVyZ+2pATOV4QMo91cN5556l14If8gV1MFJwIJCDgGmnjNR4PaoECBWTmzJm2gMdpTJtKEIIe5IK3AuT20ISFnB/AwS5hwbyCEzVOqrATw+a/b98+XyHRftq4AIaecCG8ePFiS5lwV4GcL9ocxhSwlpCxAhFIiYArpL1jxw71gOLBbtOmjW34cZmmo+7wSg3PlKAXuOSBsOCSB/u9FWHFuxTCLozNzzQfaMiIi2BcCEPGO++8U7Zs2WKpqviMikwBawkXKxCBpAi4QtofffRR7MQ8evRoR9DDA0Gftq1MKo469rlyImElpoDFhhUfvAPvENOjDRPdHgcNGmTrbUBnVMRbBFPA+rwwOXzgEEhK2rhsWrFiheUPr8c6P3X8zBGNpz1FkBrVSYH3iCbtgQMHOmkaiLrxKWCRGwTJrRLD5OF/bdeM4vektZ/26aefHvPTnjJliqX8ia6FCL1nCli/tcnxg4BAUtKO96O28++4OIwv8N9GO0TXOf0CCnyvYQdH++7duwcBQ8cyxhMWohjhUgfzSVASUiWbMDxcnn/+eeX9o90ely9fbolNvGshTC3wkmEhAkQgNQJJSRsPHeyvVj8dKJNI2tdcc40iXYQ2O708A8nD3on2yKUR5gLCatCggYrstOMDHQQs4PYI105svPDTvv/++wV3HFYFgTjw3w+7zq1w4N+JgBUCSUkbZgmYNax+l19+eVLzCPJfgHRxenSaexmXXPqkjSCNsJcrrrhC+TGHrcDM1bRp05if9vDhw9P6acPDBG9mJO2wrQTOJ9cIuHIR2aNHj5i7nx2vgvhJ4cSlTTJ9+/bN9XyN6y+spA2gtZ823sS0n/YXX3yR1N5N0jZuaVIgQxFwhbSRw1kTL5IHOSkIoddtkYgo7CUdaSOaMgwh4CDkfv36KfNH0aJFk349h6Qd9pXO+eUKAVdI+7ffflP2TJAvLiXtFpzMtEcK/LyDHBVpd87pSPv8889XybTCUuD2CG+ZZIWkHRYtcx5uI+AKaUPom266SZE2AjCQX8ROmTp1qvKkQDtcZkWhRIm00+mTpB2F1c455gIB10gbiYbwOqz9uK2+KIM82cj8h/pITLRu3bpczM/4Pkja/19FJG3jlyoFNAQB10gb88OrsD45I2kUIv4Sc2bD7Q2+uSBqEDbqjxkzxhB43BeDpE3Sdn+VcYQwIeAqaQMofFBB5yHRATfwTW7evLnUq1dPXUzpi0fUcxr2HnRlkLRJ2kFfw5TfWwSOIG0Ey+Bn9yMISAaF+shkl67AVIILyXiCjo+0RDDNrbfeKmvXrvV29gaMRtImaRuwDClCgBCIkTYiF3/++Wf1g8nCTkHObNRfs2aNneoqMg6f50JSKPhgDx48WHD56DTU3dZgAalE0iZpB2SpUkxDEAjk19gNwS4nYpC0Sdo5WUjsJDIIkLR9VjVJm6Tt8xLk8AFDgKTts8JI2iRtn5cghw8YAiRtnxVG0iZp+7wEOXzAECBp+6wwkjZJ2+clyOEDhgBJ22eFkbRJ2j4vQQ4fMARI2j4rjKRN0vZ5CXL4gCFA0vZZYSRtkrbPS5DDBwwBkrbPCiNpk7R9XoIcPmAIkLR9VhhJm6Tt8xLk8AFDgKTts8JI2iRtn5cghw8YAiRtnxVG0iZp+7wEOXzAECBp+6wwkjZJ2+clyOEDhgBJ22eFkbRJ2j4vQQ4fMARI2j4rjKRN0vZ5CXL4gCFA0vZZYSRtkrbPS5DDBwwBkrbPCiNpk7R9XoIcPmAIkLR9VhhJm6Tt8xLk8AFDgKTts8JI2iRtn5egccOvX79enn/+eWnbtq2cf/75cvbZZ0uTJk2ke/fu8umnn8qBAweMk9lLgUjaXqKdZCySNknb5yVozPD4Vuxdd90lhQsXlvgPfyf+e+3atWXKlCnGyO21ICRtrxFPGI+kTdL2eQkaMTw+En7OOefEyLpcuXLSsWNH9RHw119/XX0IvGnTppIvXz5VJ3/+/NK/f38jZPdaCJK214iTtJMi/ueff0qJEiWkS5cuPmuEw3uNwJ49e+S8885TZJw3b1658847Zdu2bUeJcfjwYZkzZ46ccsopsbog9KgVkrbPGo/SSRsPHU5UyQpJ2+eF6OPwffr0iZHwwIEDBeskXcEaOvnkk1UbbPQbNmzwUXrvhyZpe4/5ESOmI+0PPvhA3n//fZ8lzM3wP/zwg2CuVatWlZ07dx7VKUk7NzgHrReshbJlyyoCvuSSSywJW89v5syZ6lSOdj179gzatLOSl6SdFXzZN05H2tn37n8PW7dulbvvvltdLhUqVEhdNJG0/deLKRK8++67MTv2hx9+6Eishg0bqrbHHXecHDx40FHbIFcmafusvbCS9v79++XVV1+VihUrqhPR5ZdfLkuWLEmJNk/aPi9En4a//fbbFfFiQ9+xY4cjKXARqT1LFi9e7KhtkCuTtH3WniZtKzuez2I6Gn769OnKtxYP1GmnnSYfffSRHDp0KG0fJO3/wgMs3nzzzaSXcY4UEYDKF198sVonNWrUcCztpEmTYqT93nvvOW4ftAb6Poik7bPm2rVrJ0WKFJErr7xSfvrpJ5+lyW74n3/+Wdq0aaPcsmCnxKXSX3/9ZdnpggULVPAETCjdunVLWX/kyJHyyy+/WPYX1ArY2MaMGaMITL/2v/baa6EOJoHPNeYKU4fTgnWjT9ovv/yy0+aBqb9u3Trl/liqVClZu3atkLR9Vt3mzZuVi1PBggUVaeFSJZm7k89iph0eNurevXtLsWLFpECBAvLPf/5TNm7caCnyb7/9JrfddptqU7RoUXnggQdSviKvXr1aihcvLuXLl1cn97AVvXHBlFS5cmWBR4V2batTp47MmDEjbFNW8zn11FMV8TZq1Mjx/OJJ+6WXXnLc3vQGeOPq16+flCxZUh2Err/+euV9RdI2RHOwyV122WXK/lupUiUZOnSowC5scsHlD17jTzjhBPXgNW7cWObNm2cpMk7fzz33nCCAAovxmmuukeXLl6dsB9NR+/btY6cqbHJhKdi4br311qQbF/yXYbctXbq0CibBW1nY3jTOPfdcpdezzjrLsUphhtMn7bfeestxe1MbYL2PHTs25tYIH/YvvvgiJi5J2yDN4fUYbn769IET1ueff26QhP8V5auvvpIGDRqoh+akk04S2BStbvCxGD/++GM5/fTTVbu//e1vMnXqVEs3r1mzZsUi4XDS3rJlixIEeG3atMlIfKyE2rt3rzz77LO2Ni74IXft2lWOOeYY9bbxyCOPCEK+g1aS3WvcdNNNai3g1d+OKS1+zi+++GKMtBF0E4aycOFCZSrUb1zDhw8/yjxG0jZQ0zhhDRgwQMqUKRM7Ya1cudIISWFT69ChgyIQBDbgNf6PP/6wlA1+2s2bN1fkW6FCBRk8eLDs27fPsh2SA+loOTzc8a/B77zzjnorAfEHpWDj+uSTT0Tbcv/+97/b2rgwv2+++UYuvPBCRVTwd3/77bctN0oTcMEGBbPf448/fpQ4w4YNixGv0wMK7oE04WOMIJd4UyHuuNKZCknaBms6/oQFe/HDDz+c1MfZiynAvvbEE08o+xpe1W+88UaBndmqwE+7R48eMT9tZGrTJ2Wrtvg7wpT1KzBeoTXR46QJ4sLfYBNfunSpne58rZO4ceHyzM7GFS803mZGjRol1apVU3O/4IILVGi3qWXNmjXKXq2jF1etWnWEqFgLeHvA36+66irLty7deNmyZerggHZBTn2AzUabCnG6btWqVVpTIeZP0jZ1tcfJ9e2338pFF10UO2HBfmdlisjVtBI9GurVqydffvml5cOl/bQR+KD9tL///ntHYm3fvl2OP/54NW+c0OMzu2ED02QOH3CTXSaz3biSgYZN69FHH1WEB/Lq1KmTIKWpSQVpVKH/+Cx9uJtILDiFax2/8cYbllOAGaV+/fqxDTvR/x/+3jhkmFy0qTCTNy6StsmajZNNn7BOPPHEmIvU7NmzXZU+3qOhSpUqggfKKpcxFiMuiHTGtlq1asmECRMs/bSTTQQkBE8UnO5xAtHEDFMRvE10UAZOsLrcf//9alMxoSQLMHK6cVnNAydXECE2NdiFn3rqKYF5zc+CNQKzGd6A4gkb/463NISgxxdszlgn+Du8qGA6S3Uowdsnsv3pfh966KGjpnrLLbdIzZo1Zdy4cUZu5vqNC4cZJ6ZCPVGStp+rO4OxccJ67LHHlD0ZJyz4b8KPM5dFezTgAbJyxYsfV/tp48GEn/bTTz+dEwL5/fffBTKhgLiRHF8/tAiR1wWbGMhLP/i5xMRJX4kbFwKMMt247I6Ly9q6desqXDRhWQU02e3bST1cDCNgLJGs4/8bciZu/jBvVa9ePdYOXiW4qJ02bZpAryBg+PBjY9J9wUSXjNxxuMAbGkixWbNm8t133zmZgmt1sY6zMRWStF1TjTcdw54Mv00QJBYy/DmzfSWMt6/ZccXTM4WfNk48Tv20M0EKmxZO3SBmnFJgekABQcF0ox9o2An9KIkBRs8880xONi47cwER4g5AExYSMHlJWPAoiifedMSNC8jEAt9+uH/qnNmp2uOCHl+2SWcixOm9V69eKnANa+WOO+7wzdMI9xaJKR2yeePiSdvO02BwHfhv4pNMWOBIVwn/zkxOWBMnTnTs0QCSgJ+2vhBESDLs714U+CvjdKkL5NAPOU62+oIPG9n8+fNdFynTACM3BPOasLDeQKJWX5yJJ2H49ic7ZOic2UgshlQI2Jjx1oY19o9//EMGDRoU26jtYIcLy6uvvlqduuEuio8qeOVpgrngTUGbCu2mdLCaF0nbCqEA/B3k+Z///EdF0mFxwuYHf08npXPnzo7sa5n4aTuRx0ldbTLRqTqxAekC2ypMPK+88oor9k29cekAIy83LiuMQFgtW7aMERb8mnNNWNggrrvuulia1HSna/wNBIzgKJw07VweY/PFxWMmBxGND8bBpSi8jyDDGWecIchbYmd8K4xT/X3FihXSunXrWEoHvHE59UNP1TdJO1OtGNgOt+a4iNOvhAgRtxt8Atcr2NysSjI/bRMCPfBQw48Z/u26QFbtToZXZDsuilbzj//7119/7TjAyEn/uajrJmHB9ILToxVRYzPFqRkmAqeZ/HKBge4DGxb8/I899lhFpnAxzHW+H8zvwQcfjJkKcSlqJ6WDk3mStJ2gFZC6CAmH3RcLE6HisO9me8JCAA2+0wf7OezoN9xwQ85JMNfwalcykEp86LuVB4yVHPEbFzxbcJo3YeNKJzdOrLkiLGwEuOzDZXg6wsYbDu5dYMLzykXVSnf4O/L94FIT6WBxwLn33nsdmVySjYE1NWLECJXSAZuU3ZQOduRNrEPSzgS1ALTBg4VIQYSK48FC6Dgi8Zy+Emo/bf15J1z24SF02o8fkIGoEDYPbxP9FoH5wK8bpON0DkHcuBJxT0ZYThKUAQOcHtNdFiKtAS7GTf8M2KJFi+TSSy+N5ftBRsVM8v3AxVT7jSND4+jRo13dpEjafrCJh2OCuOD3ildCnABatGghP/74oy0JEv20YTfP9pRqa2AXK+GiFpsYsEAODzslyBtXqvmBsHSCMnib2CEsvMHpBE+JJ2z4ZOOiEK6NTqM87ejArTrQ7fjx42P5fjA/ZFS0s6Ej2hNuh3C9xRsXwvS9eOMiabu1GgzrFzZrhJDjlRC3/Pfcc0/KV0KdByHeTxsXTmEoeKjgFoeHEwRjVeB5ohP4IMAoDBuXnnNigrJ0hIVvlepvOcYTNrw7YF4IQhqBdLqGJ0t8RsVrr702ZUZFvG2AoEHUIGwkvQKBe1VI2l4hbcg4uLWHeQAnTYQYDxkyJHYySkyZaicPgiHTciyGlTdCpgFGjgUxoIFOAasTlMEbRKeAxV3Ifffdp+4xNFnDNAI3U2xgXpwsvYQIJh3kMsGbAy6x4/P9wC6PbJYw/wALmET8iL4laXu5IgwZC4SFU6YOHYYfKVzidB4EuylTDZlOTsXAxmU3ZWpOBzagM52gDISFS0Z4QejPgYGk8P/gGjp37tysXPAMmKqlCJgjMiricIPkXPAPx+Ui/huXjbh09MtUSNK2VF94K4CgEGqOE5aOMLSbMjWsqOBVHyYkJylTw4aFTgGrXUeR3x2fjrPrPhoWPHCyRvpfRHnCEwYRv9jI/HRbBLYk7bCssCzmAT9SBF44SZmaxXBGN0WCKjyciHCMcgFh4USJ02UmHhVhwm7Xrl3KxxwBMyYUkrYJWqAMxiAA0sapKts8LsZMKAtBEDoODxMWsxAgaZulD0rjMwIk7f8qgKTt82JMMTxJ20y9UCqfECBpk7R9Wnq2hyVp24aKFaOAAEmbpG36Oidpm64hyucpAiRtkranCy6DwUjaGYDGJuFFgKRN0jZ9dZO0TdcQ5fMUAZI2SdvTBZfBYCTtDEBjk/AiQNImaZu+uknapmuI8nmKAEmbpO3pgstgMJJ2BqCxSXgRIGmTtE1f3SRt0zVE+TxFgKRN0vZ0wWUwGEk7A9DYJLwIkLRJ2qavbpK26RqifJ4iQNImaXu64DIYjKSdAWhsEl4ESNokbdNXN0nbdA1RPk8RIGmTtD1dcBkMRtLOADQ2CS8CJG2Stumrm6RtuoYon6cIkLRJ2p4uuAwGI2lnABqbhBcBkjZJ2/TVTdI2XUOUz1MESNokbU8XXAaDkbQzAI1NwosASZukbfrqJmmbriHK5ykCb731lnTr1k327dvn6bgmDsbPjZmoFX6N3UytUCoiYAACJG0DlJBEBJ60zdQLpSICviNA0vZdBUkFIGmbqRdKRQR8R4Ck7bsKSNpmqoBSEQEzESBpm6kXnrTN1AulIgK+I0DS9l0FPGmbqQJKRQTMRICkbaZeeNI2Uy+UykUE9uzZI5s3b1Y/u65927dvV/V37NjhomRmdU3SNksfWhqStpl6oVQuIjBkyBDJkyeP+iGYxk5p1qyZqn/llVfaqR6KOiRtM9VI0jZTL5TKRQTiSTtfvnwyefJky9FI2pYQsYJHCJC0PQKaw5iDQDxp4/RcrVo1gfkjXSFpm6O/qEtC0o76Cojg/BNJG8R98803y+HDh1OiQdKO4EIxdMokbUMVQ7HcQyCetNu2bats1TCTfPLJJyTtOARo03ZvDWbTM0k7G/TYNpAIxJP2+vXrpXLlyoq4QVLbtm1LOieetAOp6lAKTdIOpVo5qXQIxJP2X3/9JR988IE6aYO4u3TpktRMQtLmmjIFAZK2KZqgHJ4hkEjaGPimm26KmUk+/vjjo2QhaXumHg5kgQBJm0skcggkI+2tW7fGzCRVqlQR/Hd8iRppI4gIOFx22WWRWx+mT5ikbbqGKF/OEUhG2hjko48+iplJOnXqdISZJCqkffDgQRk+fLhUqlRJjjnmGLnrrrtyjj87zA4BknZ2+LF1ABFIRdqYCsgatu28efMqEtclCqT95ZdfSt26ddX8a9SoIe+//35aN8gAqj4UIpO0Q6FGTsIJAulIG2YRmAVAXPAq+f3331XXYSbttWvXSvv27dVbRokSJaRfv36C/CwsZiJA0jZTL5TKRQTSkTaGxUWk9ibp0KGDOm2GkbT//PNP+fe//y3FihVT8+3YsaNs2LDBReTZdS4QIGnnAkX2ESgErEgbk+ncuXPMTAKXwDCRNjahUaNGqfB9vFHUr19f5s6dGygdRllYknaUtR/RudshbQTZINhGm0nOPvvsUGT5mzdvnjRq1EjNBWagkSNH0m4dsOeApB0whVFc+wggV3ay0HQ7pI1R0FabSXQq12SpWadNmya//PKLfcF8qPnrr79K165dJX/+/FKkSBF5+OGHZffu3T5IwiGzRYCknS2CbG8kAhMmTJBTTjlFke78+fOPkNEuaaMRiE4TdrJ82riww4UliLB3796ya9cuo/DYu3evDBgwQEqVKqU8Ytq1ayerVq0ySkYK4wwBkrYzvFjbcAR++OEHFRACgq1QoYKAoOF7HF+ckDZStmrbb6qPIHz33XfSpEmTmCnlzTfflEOHDvmO1Icffig1a9ZUcsG8M2PGDN9logDZI0DSzh5D9mAAAnDV6969uxQoUEAKFiwo99xzT8oc2U5IG1ObOHFizEyS6ss1uNwbO3as8m8GSdarV0++/vprX5BZsmSJXHrppepkXbFiRRk6dOhRG5cvgnHQnCBA0s4JjOzELwQOHDgggwcPlvLlyyuybN68uSxdujStOLB14wSNX7oc2vGdIKwb9f/444+0fcNc0rdvX+XvDNMMcpqsW7fOE3jgU37nnXeqjatQoULSs2dPy487eCIYB8kpAiTtnMLJzrxEYOrUqXLmmWcqsj7ttNPUidguCbstJ1K+wsdbB6w88cQTAr9oNwo2rkGDBkm5cuUUFi1atLDcuNyQg316gwBJ2xucOUoOEVixYoW0atVKvf6XKVNGnnvuOdtfVc+hGLa6mj17tvKDBpmedNJJMnr06JxuLPEbV+3atWXSpEk57d/WJFnJUwRI2p7CzcGyQWDnzp1y//33S+HChVUyo9tuu002b96cTZeetMVFKC4ndXj8xRdfLAsWLMhqbGxcV199tdq4ypYtK88//7yxG1dWE2XjoxAgaXNRGI+Azjx3/PHHqxMrPDUWLlxovNyJAsIdEG6BRYsWVZvOLbfcIr/99pujecC23qtXr9jGdfvtt8uWLVsc9cHKwUaApB1s/YVe+i+++ELOO++8UGWeW7lypbRp0yZm3hk4cKDAnzpdiU+Zio2radOmAldDlughQNKOns4DMeM1a9bEMs+VLFkydJnncGH62Wefyd///ne1IdWqVUulgk12kYqNS6dMPfnkk2XcuHG0WwdiFbsjJEnbHVzZa4YIwKUOmeeKFy+uQq6ReQ6eGGEt+/fvl1dffVUFAsE+ffnllwsChFDCvnGFVaduz4uk7TbC7N8WAjhhvvfee1K9enV18mzQoIHMmTPHVtswVEJwUI8ePZR/NX7wjonKxhUG/Xk5B5K2l2hzrJQIwIf52GOPVZn1kHkuMfQ8KtD9+OOPcsUVV0Ry44qKjrOdJ0k7WwTZPicIgLQRRdilS5ec9BfkTvDWsXjx4shuXEHWnReyk7S9QJljWCJA0raEiBWIgEKApM2FYAQCJG0j1EAhAoAASTsASoqCiCTtKGiZc8wFAiTtXKDIPrJGgKSdNYTsICIIkLQjomjTp0nSNl1DlM8UBEjapmgi4nKQtCO+ADh92wiQtG1DxYpuIkDSdhNd9h0mBEjaYdJmgOdC0g6w8ii6pwiQtD2Fm4OlQoCkzbVBBOwhQNK2hxNruYwASdtlgNl9aBAgaYdGlcGeCEk72Pqj9N4hQNL2DmuOlAYBkjaXBxGwhwBJ2x5OrOUyAiRtlwFm96FBgKQdGlUGeyIk7WDrj9J7hwBJ2zusORLNI1wDRCBrBEjaWUPIDnKBAE/auUCRfUQBAZJ2FLQcgDmStAOgJIpoBAIkbSPUQCFI2lwDRMAeAiRtezixlssIkLRdBpjdhwYBknZoVBnsiZC0g60/Su8dAiRt77DmSGkQIGlzeRABewiQtO3hxFouI0DSdhlgdh8aBEjaoVFlsCdC0g62/ii9dwiQtL3DmiPRPMI1QASyRoCknTWE7CAXCPCknQsU2UcUECBpR0HLAZgjSTsASqKIRiBA0jZCDRSCpM01QATsIUDStocTa7mMAElb5MCBA7Js2TKZOHGijBo1Sj755BNZunSp7N+/32X02X2QECBpB0lbIZY1yqS9Y8cOeeKJJ6RGjRqSN29eyZMnT+yH/65evbo89thjsnXr1hCvAE7NLgIkbbtIsZ6rCESVtL/55hs56aSTjiDp8uXLKwKvVKmS5M+fP/a3ypUry/Tp013VAzs3HwGStvk6ioSEUSTtuXPnSunSpRUpFyxYUG655Rb57rvvlJkE5eDBg7JixQp54IEHpGjRoqpekSJFZPLkyZFYE5xkcgRI2lwZRiAQNdLevn177IRdpkwZmTJlSlo9gOBxAgdxlytXTjZs2GCE3iiE9wiQtL3HnCMmQSBqpA0bNQg4X7588uGHH9paE59++qmqj3Y4lbNEEwGSdjT1btyso0Tae/fulSpVqijyveiii+Tw4cO29IF6LVq0UO2KFSsm27Zts9WOlcKFAEk7XPoM7GyiRNpz5syJXS6+/PLLjnQ2duzYWNsxY8Y4asvK4UCApB0OPQZ+FlEi7cGDB8eId/78+Y50t2nTpljbXr16OWrLyuFAgKQdDj0GehZ47f/4448FF3INGjSQ1atXB3o+VsLfd999ingLFCggv/76q1X1I/4Oj5JSpUqp9m3btnXUlpXDgQBJOxx6DOwsEPF31VVXqQs2+CUfc8wxUqJECfn3v/8tu3fvDuy80gl+xx13xNz3EFjjpBw6dEiOP/541R72bZboIUDSjp7OjZgxLtHuvfde5XcMH+V//etfglf/2bNnS8OGDRUpIRIQ4dw4XYap3HXXXWp+hQoVks2bNzuaGny49Um7Xbt2jtqycjgQIGmHQ4+BmQXyaLz22mvqtIgQ7UsuuUQWLVp0lAlg5MiRUrVqVUVuF154oSByMCxlwIABal6YP940nBRsdtrt7+6773bSlHVDggBJOySKNH0asFvPmDFDzj33XEVYp5xyiowbN07wup+q7Nq1Sx5++GHl3gazSdeuXUMRVPL555/HLhNHjBjhSHWTJk2KtX3jjTcctWXlcCBA0g6HHo2exS+//CLXXnutOiEibPupp54SeIvYLStXrhSYApCHA+379+8ve/bssdvcuHqQvWLFiop8mzVr5ki+G264IXaJuXHjRkdtWTkcCJC0w6FHI2eBk/IjjzwixYsXVyflzp07y/r16zOWFSfUOnXqxE7qH3zwQdqTesYDedAQ+UR0RCQ8Z+wUmIhg/6fniB20wluHpO2xbmEmGDhwoAwfPlxdvIWx4OLw7bfflmrVqim7baNGjQS5M3JRtE38uOOOU+R16aWXyuLFi3PRtSt96I3ryy+/PKJ/pFlF1j7MoUKFCpb4IHEUMv/ppFHIux1fsBn26NFDfv/9d1fmwU7NQYCk7bEucMFWuHBh9aqPf+Ii7pVXXlG2WrvhzB6L7Gg4RPtdcMEFMe8PkLdd7w+4v8GLxI6ftvY+AYY4fXbr1k22bNniSFY3K2PO0LXeuODml1g+++wzZa8HEcPNsW/fvkfNAYmlEIxz7LHHqnpYN9jwE8tzzz2nNkjUGzRokOzbt8/N6bFvHxEgaXsIPk5LCCCpVauWIBy5U6dOsYcRxIM8FM8//7wiraAROE56MH/ADAJzyKOPPio4ZTopo0ePjrVHQiU7fto//fSTXHnllYqwkAXvpZde8p2wEjeud955J6UZByYffeIGKWMTOuuss6RJkyZyzjnnxEhdE3u6i0t88aZ27dqK3NHH1KlTA7eOnKyXqNYlaXuk+b/++kvq16+vHsp49zX8f2RvQ9Y2BJfggQPx1atXT+Aatnz5cqPttrhQfPLJJ5XvME6B1113naxatSpjVEF48NMGCZ944onKTzudh4keCF4Vp59+usLvzDPPVJh6vfFh48JGrDcuuxsPfLXhs65P0/FfrsG/A9t//vOfggtZq4ITNjb+smXLKgxbtWql1hBLeBAgaXuky/vvv18RyjPPPJNyRDxwOHnhVR8+ynjo4HGBE9fjjz8uP/zwgy0C82JKIFK47NWsWVPNq27dusqlLxcFpoW33nrLsZ828HvhhRdUvmlgd/XVV6tvLrpdEjeu9u3bZ7Rxwavkq6++kmHDhsmzzz6r/glM7bxxJM4R9yW33367CpVHABPWn9PoS7dxY/+ZIUDSzgw3R63wpRGcvq644grb9l1EvuEB7tmzp0qWDxLC74wzzpCHHnpIFi5caLsvR8LaqIyvq8BVDWSNtwOQi/7aio3mtqsk89O24+aGkytsyCAsvNkgsRJsw7kuyTaumTNn5nqYrPrDOmnatKlaOwhogj3cDV1lJSQbO0KApO0ILueVkRAINks8MHYIJ9kIIIdvv/1WHnzwQWUP1xFxOOWCkGBS8OJBTDy9IfGRFzmd4ecNP23t5w2zEcxKVgWRlthcQFi53lywceESGRsXdOvWxmU1Rzt/h5kIdyja++T888+XRG8WO/2wjhkIkLRd1ANe85s3b65O2bC55qLgAQQZwV6KyyZN4MjT0b17d5k1a5bALS6XBUn7YSeF2QHjIcGT0/DrXMiT6KeNL75Y2a3x93gzDiIygZFVu1Ty6lM8Lo5hdnDrFJ8LvBL7gBmnX79+UrJkSaVHBOqsWbPGjaHYp4sIkLRdBBd2SZzEcCJNVkDqmZKH7g/eE7gIBBnpL3fj5Hfbbbcp7wEQbqYFsiVe8MHUk63MmcqDdnijGDp0qMT7aX///feWXcJejEhMXOqBsJxemAJHP+zllhPLoMK6deukQ4cOar3A1bBPnz7yxx9/ZNATm/iBAEnbJdThIYKTGLxAkr3Kg/hArLgsytXJGN4FCNxBTmqc7rFhwCMBrniIunMS+o3NAKk/TXKli1cVzDKw9yNTHmzXdv204Q+vXRPhIw3XxHQXfdATNircJWjPFL83rlwtWWRUhEcT5gVPnffee8+Yi+5czTGM/ZC0XdDqzp07le0ZeTJSeS/AJxknPngauHFyXbt2rQqyaNy4sSI1PJjwEb/++uvl/fffT0lUmZKhCzDa6hJmmsTNxc4miAhNnQIWATDJfKl1rm9TNy5bAFlUwtvem2++KSeccIJaI4gVmDdvXi66Zh8uIUDSzjGwIGD46uJBx8OQrOBiDfZhXAx5cZH322+/KZPCZZddpk6mOlCjdevWiqzgWQGzw5AhQ5TZIVXK1BxDldPuEs04U6ZMsdwMccGrw+2BCSI58YYEPOA3HR9t6TTvdU4n50Fn8NTp3bu3FC1aVL2lwS/c6Vd1PBCTQ/wvAiTtHC8D+BeD9Dp27JiUNOBLjPzQIE+49HldkJsCUXW4TMQDCrLCP5EqFf8Oj5Tx48dbEp7XctsZT/tp68AS+GnbCSyBeQRmEphLYOeNz/Vtcl4TO5g4rQMTW5s2bdRbIHDMJlDK6disbw8BkrY9nGzVAkHAJHLqqaemDGRAfmiQI27x/S4ItkDEIdzitCeEHVc6v+W2Gh85SHRgifbTthNYAoKCyQTeFXCRc8NsZSW7KX+fPn26ujOwE41qisxRkYOknSNNw7sAl46JYerx3SNBEOzLIEkv/KrtTg0mEmwkeFDDVOAaqQNL4Kf9+uuvWwYkwSyANw8n+b7DhBnnYj4CJO0c6Qj+uunC1GETRWg6kt/D5cqkElbSBsbaT1sHlsA18osvvkgJP0nbpJVJWZIhQNLOwbqwClPHKyYS98BeioAQ00o60gbphcFMALMP/Nlh+sCdA9LhJiskbdNWJ+VJRICkneWawA07Lq7ShanD9Q6ncEQsmljSkTZs3sh9EpYLOfhp33rrrSm/oEPSNnGFUqZ4BEjaWawH+LgiCRRO0KnC1JGjAjZSZOpzEtyShViOm6YjbbgBYsNB7pMoFJJ2FLQc7DmStLPQH6IP04Wpw5UMkXQIFUZaVVMLSfu/miFpm7pKKZdGgKSd4VpAEAY8RZAxLVV+D3zYAPZTZIAzuZC0Sdomr0/KdiQCJO0MVgTC1BGMguRDqYI33A5Tz0DslE1I2iTtXK4n9uUuAiTtDPBFtCNO0Ih+TFYQpo5oMq/C1DOYwhFNSNok7WzXENt7hwBJ2yHWOkwdqS2TucIhWVGjRo3UF8L9CFN3OB1VnaRN0s5k3bCNPwiQtB3gDlMITCIwjcBEkqzoMPW+ffs66NnfqiRtkra/K5CjO0GApG0TLVw2nnfeeZZh6siQZlqYutUUSdokbas1wr+bgwBJ26Yu8PWZdGHqSFKEMPUKFSoYF6ZuNUWSNknbao3w7+YgQNK2oQuEqSOA5vLLL0+acAhh6i1btlTpLE0MU7eaIkmbpG21Rvh3cxAgaVvoAmHqyBCHX6qk8KaHqVstN5I2SdtqjfDv5iBA0k6jC5ygcbrGKRun7WQlCGHqVsuNpE3Stloj/Ls5CJC00+jimWeeSRumji9YByFM3Wq5kbRJ2lZrhH83BwGSdgpdIEwdnwSDx0iqMHV8TR2Xk6aHqVstN5I2SdtqjfDv5iBA0k6hC6TvRHa+VFGPaIbgGXwANuifZCJpk7TNoSRKYoUASTsFQhs3blRfJkeebHzNPMyFpE3SDvP6DtvcSNppNDpx4kR1Cdm8efPAn6bTLVySNkk7bMQW5vmQtC20iy9Sw2797LPPhnYdkLRJ2qFd3CGcGEnbQqn4tmDdunVV+Pq8efNCuASYMCpeqfwIQiiXeKgmRdK2oc5ly5apD8LWqlVLdu3aZaNFsKrwpM2TdrBWbLSlJWnb1P+IESNUDu0uXbqE4uvk8dMmaZO0bT4GrGYAAiRtm0pA7uybbrpJETdILkyFpE3SDtN6DvtcSNoONLxjxw6VS7tMmTLy888/O2hpdlWSNknb7BVK6eIRIGk7XA9z5sxRl5INGjRIGSnpsEvfq5O0Sdq+L0IKYBsBkrZtqP5b8emnn1ZugP/zP/+TQWvzmpC0SdrmrUpKlAoBknYGa+PgwYMq+x++UjNlypQMejCrCUmbpG3WiqQ06RAgaWe4PhDmjhzbVapUCXyYO0mbpJ3hY8BmPiBA0s4CdB3mftVVVyX9ok0WXXvalKRN0vZ0wXGwrBAgaWcFn6gsf7Bvv/DCC1n25F/zqJE2zFupCiMi/VuHHNkeAiRtezilrIUwd+TcRhrXhQsXZtmbP83TkfbMmTMFRLZ69Wp/hMvhqPC1//jjj9WHK5AvPVkhaecQcHblCgIk7RzAunTpUuncubNs3bo1B71530U60vZeGndG/OGHH+SKK65QwVEVKlRI+QFmkrY7+LPX3CFA0s4dloHtKcykjY20R48e6itE+N11113y+++/0zwS2NVKwUnaXAMqLB92+enTp4cGjf3798urr76qTtWYG1w0lyxZYjk/nrQtIWIFnxEgafusAL+G37dvn3z++efSrVs3qVq1qhQvXlz+8Y9/yI8//uiXSDkbF5vP2WefrcgamRk/+ugjyyRf+GTc2LFj5cQTT5SyZcvKn3/+mTN52BERyCUCJO1coml4X3v27JHJkyfLLbfconzMQWoIEKpXr5507NhRChYsqEL077nnnkDa55EPpnXr1pIvXz6VH2bgwIGCi2KrsmDBAmnatKmyd1euXFneeOMNS5K36pN/JwJuIUDSdgtZQ/rdvXu3unTr0KGDlC9fXhE1yPnCCy9UborwCoFXBcqiRYvk0ksvVeSF72MOHTpUYGYwvezcuVN69+6tPHiwCWFT+vXXXy3Fxrc/b7vtNoUH2j7wwAOCpGAsRMBkBEjaLmnn7rvvlmbNmkmLFi1k06ZNlqPgwgz18YObXTYFxDN69Gi57rrrpHTp0oqocYK+5JJL5JVXXpENGzak7B5mgvHjx6tshmhXp04d+eyzz7IRx7W28LdGnvMTTjhBydq4cWOZP3++5Xh79+6V5557TsqVK6dO5ddcc40sX77csh0rEAETECBpu6SFCy64QBEJfjfccIPl6zbC4nV9EK7TAo+It956S1q2bCklSpRQfRUrVkx9lHj48OG2No74MWFK6d+/vyJ9fNy4bdu2snLlSqdiuVb/q6++kvr166t5nnTSSWqTwoaTrmg/7dNPP121+9vf/iZTp0611I1rk2DHRCADBEjaGYBmp0k8aeM0N2bMmLTNMiFtmACGDRumPCPweg8iwmfRcHJ8++23c2KXxqkcX+uB2QGbwEMPPSQwR/hV1q5dqz5GgY0Em9Pjjz8uf/zxh6U4uGDFBqb9tAcPHiy4jGUhAkFDgKTtksbiSRtkios/2FBTFbukDdIC4TRp0kT5HaNveDu0b99eeT+4ZZOdO3eusoNjPHib4FSfLhw817CCmJ944gm1KYGwb7zxRlmzZo3lMMn8tLds2WLZjhWIgKkIkLRd0owm7WrVqqlTKsgONmZ96Zc4rBVpI6IPfeLSDH3B/7hTp04yYcIEWyfNXEwTJD1q1CipXr26kqFhw4by9ddf56LrlH3A5AHTR40aNdSY8HT58ssvLcfUftoVK1ZUp2u7ftqWHbMCEfAZAZK2SwrQpA1bMHyhQTgwk6SyV1uR9ubNm5XtFp4Rn376qcDm7FeBR8pjjz2mzBPYkOAuuG7dupyLg0tFXC6CdJECF654Bw4csBwHF6fxftrY2Kzs3ZadsgIRMAQBkrZLiognbdiAa9asqYgbrnTJ3NGsSBtimuZ+t2rVKmWWgbmiVKlS0q9fv5yc+oEPNqcCBQooWz2+EGTH7AM/7TZt2sT8tJ955hlbftouLQF2SwRcQYCk7QqsokwZIGmctFEQpafNJO3atTvKTGKHtF0SNatuYe6ZNWuWynSI+WJzgm09k5MtAmEQEKNd8RAos2LFCkv5tJ82LkpB9AhFt+OnbdkxKxABAxEgabuklETSxjB33nmnIja87r/77rtHjBxU0taTwFsAXAsRUYj5IcIQkYZOCjABPjBtTJs2zdIVD6aSN998M+anffHFF8u8efOcDMm6RCBwCJC0XVJZMtLGifDUU0+NmUlA1LoEnbT1PLZv3y69evVSZg1cmiLiMJ3XTDz8IOH33nvPliseLkAbNGhwhJ+2l94sLi0bdksELBEgaVtClFmFZKSNnpCkCa/wOFHC/qq9ScJC2hqtZcuWSatWrZR9GeHziEC0kwfECm3tpw1TE9z/+vTpkxM7utW4/DsRMAUBkrZLmkhF2hgOOZ21mQRpUVHCRtqYEzYkfK0ekYeYLyIRP/nkE0uzRzKVxPtpg7Dt+mm7pF52SwR8Q4Ck7RL06Uh7165dMTMJ/K0RdRhG0tbQItfHoEGDlG85Tt7Ix2I3BSwuNBFN6tRP2yW1slsi4DsCJG2XVJCOtDHkjBkzYt4kCDtfv359VrlHXJpGTruFr3n37t1VJKedFLDw00bkp1M/7ZwKzc6IgGEIkLRdUogVaWNYfAZLm0kGDBgQetLWUC9evFh9cAFkjPD+IUOGHOGDnqmftkuqZLdEwCgESNouqcMOaSOy8LTTTlNkXaRIkciQNiCH2QN5vvFlGcz/nHPOUW5+8NNGLhWYUez6abukQnZLBIxEgKTtklrskDaGRmCK9ibJJjWrS9NwvVuE4z/99NPqSzMIi8fp266ftuvCcQAiYCACJG2XlGKXtDE8Pu+lCRv/zCSftkvT8KxbfEEHLnxwE2TKVM9g50ABRICk7ZLSnJB2vJkkqqSND+nipI3c3SxEgAikRoCk7dLqGDdunMp7jYx8dgou51AfPyQ+ilohaUdN45xvpgiQtDNFju1yigBJO6dwsrMQI0DSDrFygzQ1knaQtEVZ/USApO0S+jCP9O3bV5k77BR8sR318fv+++/tNAlVHZJ2qNTJybiIAEnbJXCRR1t/KdzOELBpaw+SkSNH2mkSqjok7VCpk5NxEQGStkvgkrSdAUvSdoYXa0cXAZK2S7onaTsDlqTtDC/Wji4CJG2XdE/SdgYsSdsZXqwdXQRI2i7pnqTtDFiStjO8WDu6CJC0XdI9SdsZsCRtZ3ixdnQRIGm7pHuStjNgSdrO8GLt6CJA0nZJ95q0kU+ja9eulj98CIEuf8w94tJyZLchQoCk7ZIyNWnHZ++z++/003ZJKeyWCIQAAZK2S0rUpF28eHG5/vrrLX/NmzfnSZtZ/lxajew2TAiQtF3SJm3azoClTdsZXqwdXQRI2i7pnqTtDFiStjO8WDu6CJC0XdI9SdsZsCRtZ3ixdnQRIGm7pHuStjNgSdrO8GLt6CJA0nZJ9yRtZ8CStJ3hxdrRRYCk7ZLuSdrOgCVpO8OLtaOLAEnbJd2TtJ0BS9J2hhdrRxcBkrZLuidpOwOWpO0ML9aOLgIkbZd0/+yzzwqIu1u3brZGWLNmjaqP36xZs2y1CVMlknaYtMm5uIkASdtNdNm3bQRI2rahYsWII0DSjvgCMGX6JG1TNEE5TEeApG26hiIiH0k7IormNLNGgKSdNYTsIBcIkLRzgSL7iAICJO0oaDkAcyRpB0BJFNEIBEjaRqiBQpC0uQaIgD0ESNr2cGItlxEgabsMMLsPDQIk7dCoMtgTIWkHW3+U3jsESNreYc2R0iBA0ubyIAL2ECBp28OJtVxGgKTtMsDsPjQIkLRDo8pgT4SkHWz9UXrvECBpe4c1R6J5hGuACGSNAEk7awjZQS4Q4Ek7FyiyjyggQNKOgpYDMMcDBw7ImDFjZM6cOQGQliISAf8QIGn7hz1HJgJEgAg4RoCk7RgyNiACRIAI+IcASds/7DkyESACRMAxAiRtx5CxAREgAkTAPwRI2v5hz5GJABEgAo4RIGk7howNiAARIAL+IUDS9g97jkwEiAARcIwASdsxZGxABIgAEfAPAZK2f9hzZCJABIiAYwRI2o4hYwMiQASIgH8IkLT9w54jEwEiQAQcI0DSdgwZGxABIkAE/EOApO0f9hyZCBABIuAYAZK2Y8jYgAgQASLgHwL/D8WfF6zablEgAAAAAElFTkSuQmCC">
      iptacopan化學結構式(圖片來源:medchemexpress.com)
      iptacopan是一款首創的(first-in-class)、口服、強效、選擇性、小分子、可逆性B因子抑制劑,B因子是補體系統替代途徑的關鍵絲氨酸蛋白酶。
      目前,iptacopan正在被開發用于治療存在顯著未滿足醫療需求的許多由補體驅動的腎臟疾?。–DRD),包括C3G、IgA腎病、非典型溶血性尿毒癥綜合征(aHUS)、膜性腎?。∕N),以及罕見的血液疾病陣發性夜間血紅蛋白尿(PNH)。
      已公布的2期數據顯示:(1)iptacopan治療IgAN降低了蛋白尿并穩定了腎功能;(2)治療C3G降低了估計的腎小球濾過率(eGFR)下降速度并穩定了腎功能;(3)治療PNH顯著減少了血管內和血管外溶血,使大多數患者實現了快速和持久的無輸血改善。
      雖然諾華在腎移植治療方面已有35年的歷史,但iptacopan是腎臟病治療管線中解決CDRD的第一種治療方法。諾華的目標是通過針對這些罕見且進展性疾病的關鍵驅動因素之一來改變治療方法,這樣做有潛力延長CDRD患者的無透析生命。
      原文出處:Novartis iptacopan meets primary endpoints in Phase II study in rare kidney disease C3 glomerulopathy (C3G)
      狼人视频国产在线视频www色
    1. <pre id="lvu8t"></pre>
      <table id="lvu8t"><ruby id="lvu8t"></ruby></table>