{"id":21761,"date":"2015-07-17T00:04:19","date_gmt":"2015-07-16T16:04:19","guid":{"rendered":"https:\/\/case.ntu.edu.tw\/blog\/?p=21761"},"modified":"2018-08-01T15:54:43","modified_gmt":"2018-08-01T07:54:43","slug":"%e3%80%90%e4%bc%8a%e6%b3%a2%e6%8b%89%e5%b0%88%e9%a1%8c%e3%80%91%e4%b8%80%e9%87%9d%e6%b0%b8%e3%80%8c%e7%96%ab%e3%80%8d%ef%bc%9a%e4%bc%8a%e6%b3%a2%e6%8b%89%e7%97%85%e6%af%92%e7%96%ab%e8%8b%97%e7%a0%94","status":"publish","type":"post","link":"https:\/\/case.ntu.edu.tw\/blog\/?p=21761","title":{"rendered":"\u3010\u4f0a\u6ce2\u62c9\u5c08\u984c\u3011\u4e00\u91dd\u6c38\u300c\u75ab\u300d\uff1a\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u75ab\u82d7\u7814\u767c"},"content":{"rendered":"<p><span style=\"color: #333399;\"><strong>\u25a0\u6240\u8b02\u9810\u9632\u52dd\u65bc\u6cbb\u7642\uff0c \u5982\u4eca\uff0c\u96e2\u7814\u767c\u51fa\u6709\u6548\u7684\u4f0a\u6ce2\u62c9\u75ab\u82d7\u9019\u689d\u7d42\u9ede\u7dda\uff0c\u6211\u5011\u9084\u8ddd\u96e2\u591a\u9060\u5462\uff1f<\/strong><\/span><\/p>\n<figure id=\"attachment_21762\" aria-describedby=\"caption-attachment-21762\" style=\"width: 300px\" class=\"wp-caption alignleft\"><img fetchpriority=\"high\" decoding=\"async\" class=\"size-full wp-image-21762\" src=\"http:\/\/case.ntu.edu.tw\/blog\/wp-content\/uploads\/2015\/06\/vaccine.jpg\" alt=\"credit \u662f NIAID\uff0fGSK\" width=\"300\" height=\"300\" srcset=\"https:\/\/case.ntu.edu.tw\/blog\/wp-content\/uploads\/2015\/06\/vaccine.jpg 300w, https:\/\/case.ntu.edu.tw\/blog\/wp-content\/uploads\/2015\/06\/vaccine-150x150.jpg 150w\" sizes=\"(max-width: 300px) 100vw, 300px\" \/><figcaption id=\"caption-attachment-21762\" class=\"wp-caption-text\">credit \u662f NIAID\uff0fGSK<\/figcaption><\/figure>\n<p><strong>\u64b0\u6587\uff5c<\/strong>\u99f1\u5b9b\u7433<\/p>\n<p>2014\u5e74\u4e09\u6708\u5e95\uff0c\u4e16\u754c\u885b\u751f\u7d44\u7e54\u6b63\u5f0f\u767c\u4f48\u975e\u6d32\u5e7e\u5167\u4e9e\u5883\u5167\uff0c\u7206\u767c\u4e86\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u611f\u67d3\u3002\u7576\u6642\uff0c\u9130\u8fd1\u5e7e\u5167\u4e9e\u7684\u570b\u5bb6\uff0c\u5305\u62ec\u8cf4\u6bd4\u745e\u4e9e\u8ddf\u7345\u5b50\u5c71\uff0c\u4e5f\u90fd\u51fa\u73fe\u7591\u4f3c\u75c5\u4f8b\u3002\u516d\u6708\u6642\uff0c\u4e00\u76f4\u5728\u75ab\u60c5\u6700\u524d\u7dda\u652f\u63f4\u7684\u7121\u570b\u754c\u91ab\u751f\u7d44\u7e54\u8b66\u544a\u75ab\u60c5\u5df2\u7d93\u5931\u63a7\uff1b\u516b\u6708\u6642\uff0c\u4e16\u754c\u885b\u751f\u7d44\u7e54\u6b63\u5f0f\u5ba3\u5e03\u4f0a\u6ce2\u62c9\u75ab\u60c5\u70ba\u5168\u7403\u885b\u751f\u7dca\u6025\u4e8b\u4ef6\u3002\u81ea\u6b64\uff0c\u4f0a\u6ce2\u62c9\u75ab\u60c5\u50cf\u662f\u88ab\u9ede\u71c3\u5f15\u4fe1\u7684\u706b\u85e5\u5eab\uff0c\u4e00\u767c\u4e0d\u53ef\u6536\u62fe\uff0c\u4fdd\u5b88\u4f30\u8a08\u6709\u5169\u842c\u4eba\u88ab\u78ba\u8a8d\u611f\u67d3\u4f0a\u6ce2\u62c9\u75c5\u6bd2\uff0c\u8d85\u904e\u516b\u5343\u4eba\u56e0\u800c\u904e\u4e16\u3002<\/p>\n<p>\u5728\u75ab\u60c5\u5df2\u8da8\u5e73\u7de9\u7684\u4eca\u65e5\uff0c\u56de\u982d\u770b\u53bb\u5e74\u5931\u63a7\u6642\u7684\u4eba\u5fc3\u60f6\u60f6\uff0c\u4e0d\u8ad6\u662f\u5c0d\u4e00\u822c\u5e02\u4e95\u5c0f\u6c11\u9084\u662f\u524d\u7dda\u9632\u75ab\u5de5\u4f5c\u4eba\u54e1\uff0c\u90fd\u662f\u4e00\u5834\u4e0d\u60f3\u518d\u7d93\u6b77\u4e00\u6b21\u7684\u5669\u5922\u3002\u5982\u4eca\u75ab\u60c5\u5e73\u6b47\uff0c\u91ab\u7642\u7814\u7a76\u76f8\u95dc\u4eba\u529b\u5728\u5598\u53e3\u6c23\u7684\u540c\u6642\uff0c\u4e5f\u7d42\u65bc\u80fd\u597d\u597d\u91cd\u65b0\u8a55\u4f30\u5c0d\u6297\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u7684\u7b56\u7565\u3002\u800c\u8b93\u524d\u7dda\u4eba\u54e1\u6700\u60f3\u8981\u8ddf\u5b87\u5b99\u4e0b\u8a02\u55ae\u7684\uff0c\u83ab\u904e\u65bc\u4e00\u652f\u5b89\u5168\u6027\u9ad8\uff0c\u4fdd\u8b77\u6027\u6975\u4f73\u7684\u75ab\u82d7\u4e86\u3002\u4e00\u652f\u597d\u75ab\u82d7\uff0c\u9664\u4e86\u80fd\u8b93\u81f4\u6b7b\u7387\u964d\u4f4e\uff0c\u5c0d\u9632\u75ab\u5de5\u4f5c\u7684\u63a7\u7ba1\u4e5f\u5f88\u6709\u6548\u3002\u76ee\u524d\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u7684\u518d\u751f\u57fa\u6578(reproduction number)\u9810\u4f30\u503c\u7d04\u57281.38\u52302.02\u4e4b\u9593\u3002\u518d\u751f\u57fa\u6578\u4ee3\u8868\u8457\u55ae\u4f4d\u6642\u9593\u5167\uff0c\u4e00\u500b\u5df2\u7d93\u78ba\u8a3a\u7684\u4f0a\u6ce2\u62c9\u611f\u67d3\u75c5\u60a3\uff0c\u6703\u628a\u75c5\u6bd2\u518d\u50b3\u7d66\u5e7e\u500b\u4eba\u3002\u5982\u679c\u6709\u4e00\u652f\u597d\u75ab\u82d7\uff0c\u5c31\u7b97\u53ea\u80fd\u5920\u63d0\u4f9b\u90e8\u5206\u4fdd\u8b77\uff0c\u53ea\u8981\u80fd\u628a\u518d\u751f\u57fa\u6578\u964d\u52301\u4ee5\u4e0b\uff0c\u75ab\u60c5\u5c31\u4e0d\u6703\u5982\u6307\u6578\u822c\u8513\u5ef6\uff0c\u800c\u80fd\u5920\u88ab\u63a7\u5236\u3002<!--more--><\/p>\n<p>\u8981\u7814\u767c\u4e00\u652f\u597d\u75ab\u82d7\uff0c\u5f97\u5148\u5c0d\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u5165\u4fb5\u5f8c\u6240\u5f15\u767c\u7684\u514d\u75ab\u53cd\u61c9\u77ad\u82e5\u6307\u638c\u3002\u9ad4\u6db2\u53cd\u61c9(humoral immunity)\u5728\u5c0d\u6297\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u7684\u514d\u75ab\u6a5f\u5236\u88e1\u626e\u6f14\u8457\u91cd\u8981\u7684\u89d2\u8272\uff0c \u4e3b\u8981\u662f\u9760B\u7d30\u80de\u7522\u751f\u6297\u9ad4\u4f86\u5f62\u6210\u5c0d\u6297\u75c5\u6bd2\u611f\u67d3\u7684\u4fdd\u8b77\u7f69\u3002\u50cf\u662f\u76ee\u524d\u5e38\u807d\u5230\u7528\u611f\u67d3\u5f8c\u60bb\u5b58\u8005\u7684\u8840\u6e05\uff0c\u6216\u8005\u662f\u5be6\u9a57\u6027\u7528\u85e5ZMapp\uff08\u542b\u6709\u4e09\u7a2e\u55ae\u682a\u6297\u9ad4\uff09\uff0c\u90fd\u662f\u5229\u7528\u6297\u9ad4\u53cd\u61c9\u4f86\u9054\u5230\u4fdd\u8b77\u4f5c\u7528\uff0c\u6216\u662f\u628a\u75c5\u6bd2\u300c\u4e2d\u548c\u300d\u6389\u3002\u300c\u4e2d\u548c\u529b\u300d\u5f37\u7684\u6297\u9ad4(neutralizing antibody)\uff0c\u53ef\u4ee5\u5f71\u97ff\u75c5\u6bd2\u8ddf\u7d30\u80de\u8868\u9762\u53d7\u9ad4\u7d50\u5408\uff0c\u6291\u5236\u75c5\u6bd2\u9032\u5165\u7d30\u80de\uff0c\u6216\u662f\u5e72\u64fe\u75c5\u6bd2\u5728\u9032\u5165\u7d30\u80de\u5f8c\u628a\u57fa\u56e0\u9ad4\u91cb\u653e\u5230\u5bbf\u4e3b\u7d30\u80de\u5167\u7684\u904e\u7a0b\uff0c\u4e5f\u53ef\u80fd\u8b93\u75c5\u6bd2\u6210\u7fa4\u51dd\u96c6\u5728\u4e00\u8d77\u800c\u5931\u53bb\u6d3b\u6027\u3002\u4f46\u6297\u9ad4\u5728\u514d\u75ab\u53cd\u61c9\u88e1\u4e5f\u5728\u5176\u4ed6\u53cd\u6297\u6a5f\u5236\u88e1\u626e\u6f14\u91cd\u8981\u89d2\u8272\uff0c\u4f8b\u5982\u6297\u9ad4\u4f9d\u8cf4\u578b\u7d30\u80de\u4ecb\u5c0e\u7684\u7d30\u80de\u6bd2\u6027\u4f5c\u7528(antibody-dependent cell-mediated cytotoxicity)\u3002<\/p>\n<p>\u76ee\u524d\u5728\u81e8\u5e8a\u8a66\u9a57\u4e2d\u7684\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u75ab\u82d7\uff0c\u4e3b\u8981\u662f\u91dd\u5c0d\u75c5\u6bd2\u8868\u9762\u7684\u91a3\u86cb\u767d(glycoprotein)\u3002\u845b\u862d\u7d20\u53f2\u514b\u85e5\u5ee0(GSK)\u8ddf\u7f8e\u570b\u570b\u5bb6\u885b\u751f\u7814\u7a76\u9662(NIH)\u5408\u4f5c\u7814\u767c\u4e86cAd3-EBOZ\uff1b\u8207\u52a0\u62ff\u5927\u653f\u5e9c\u6388\u6b0a\u751f\u7522\u7684rVSV-EBOV\u3002cAd3-EBOZ\u75ab\u82d7\u7684\u767c\u5c55\u6b77\u53f2\u5f88\u60a0\u4e45\uff0c\u57282000\u5e74\u7684\u6642\u5019\uff0c\u5c31\u6709\u975e\u4eba\u985e\u9748\u9577\u985e\u7684\u7814\u7a76\u7d50\u679c\u51fa\u7210\uff0c\u80fd\u5920\u63d0\u4f9b\u975e\u4eba\u985e\u9748\u9577\u985e\u5b8c\u5168\u7684\u4fdd\u8b77\u529b\u3002\u9019\u652f\u75ab\u82d7\u4e3b\u8981\u662f\u7528DNA\u6280\u8853\u70ba\u5e73\u53f0\uff0c\u5229\u7528\u53bb\u6bd2\u6027\u7684\u9ed1\u7329\u7329\u817a\u75c5\u6bd2\u70ba\u8f09\u9ad4\u5de5\u5177\u4f86\u8868\u73fe\u591a\u7a2e\u4e0d\u540c\u7684\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u8868\u9762\u91a3\u86cb\u767d\u3002\u4f46\u7f3a\u9ede\u662f\uff0c\u9700\u8981\u63a5\u7a2e\u591a\u6b21\u75ab\u82d7\uff0c\u800c\u4e14\u5291\u91cf\u4e5f\u504f\u9ad8\uff0c\u624d\u80fd\u8b93\u9019\u652f\u75ab\u82d7\u80fd\u5920\u767c\u63ee\u5168\u9762\u4fdd\u8b77\u529b\u3002\u800crVSV-EBOV\u75ab\u82d7\u5247\u662f\u5229\u7528\u5236\u5f31\u6027\u6c34\u6ce1\u53e3\u819c\u708e\u75c5\u6bd2(VSV)\u70ba\u5a92\u4ecb\uff0c\u4f86\u8868\u73fe\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u7684\u8868\u9762\u91a3\u86cb\u767d\u3002\u4f46\u5229\u7528VSV\u70ba\u75ab\u82d7\u6297\u539f\u5a92\u4ecb\u7684\u5b89\u5168\u6027\u4e5f\u4e00\u76f4\u70ba\u79d1\u5b78\u754c\u64d4\u5fc3\u3002\u6240\u4ee5\uff0c\u96d6\u7136\u81e8\u5e8a\u4e0a\u9019\u5e7e\u652f\u75ab\u82d7\u90fd\u9032\u5c55\u5230\u4eba\u9ad4\u8a66\u9a57\u7b2c\u4e09\u968e\u6bb5\uff0c\u5927\u5bb6\u4e5f\u90fd\u5c0d\u5176\u5bc4\u8207\u539a\u671b\uff0c\u4f46\u662f\u79d1\u5b78\u5bb6\u4e5f\u4e00\u76f4\u90fd\u6c92\u6709\u505c\u6b62\u5c0b\u627e\u5176\u4ed6\u7684\u53ef\u80fd\u6027\u3002<\/p>\n<p>\u53e6\u4e00\u500b\u5e0c\u671b\u4f86\u6e90\u662f\u7814\u767c\u5168\u75c5\u6bd2\u75ab\u82d7(whole-virus vaccines)\uff0c\u5229\u7528\u6d3b\u6027\u6e1b\u6bd2\u75c5\u6bd2\uff0c\u6216\u662f\u4e0d\u6d3b\u5316\u75c5\u6bd2\u4f5c\u70ba\u6297\u539f\u3002\u5168\u75c5\u6bd2\u75ab\u82d7\u5728\u4eba\u985e\u75ab\u82d7\u767c\u5c55\u4e0a\u8ca2\u737b\u5353\u8457\uff0c\u4fdd\u8b77\u6211\u5011\u514d\u65bc\u8a31\u591a\u53ef\u80fd\u81f4\u6b7b\u7684\u611f\u67d3\u75c5\u5a01\u8105\uff0c\u50cf\u662f\u5929\u82b1\u75ab\u82d7\uff0c\u75f2\u75b9\u3001\u816e\u817a\u708e\u75ab\u82d7\uff0c\u6d41\u611f\u75ab\u82d7\u7b49\u3002\u5168\u75c5\u6bd2\u75ab\u82d7\u56e0\u70ba\u63d0\u4f9b\u591a\u7a2e\u75c5\u6bd2\u86cb\u767d\u8cea\u8207\u75c5\u6bd2\u57fa\u56e0\u9ad4\uff0c\u56e0\u6b64\u5728\u63a5\u7a2e\u4e4b\u5f8c\uff0c\u80fd\u5920\u8a98\u767c\u8f03\u5ee3\u800c\u591a\u9762\u7684\u514d\u75ab\u53cd\u61c9\uff0c\u81ea\u7136\u4fdd\u8b77\u6548\u679c\u8f03\u4f73\u3002\u4f46\u662f\uff0c\u91dd\u5c0d\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u7684\u5168\u75c5\u6bd2\u75ab\u82d7\u7814\u767c\u537b\u4e00\u76f4\u4e0d\u898b\u6709\u597d\u6d88\u606f\u3002\u525b\u958b\u59cb\u6642\uff0c\u7814\u7a76\u4eba\u54e1\u5617\u8a66\u7528gamma\u5c04\u7dda\u6bba\u6b7b\u7684\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u70ba\u6297\u539f\u7684\u75ab\u82d7\uff0c\u537b\u5b8c\u5168\u5931\u6557\u3002\u4f46\u4eca\u5e74\u56db\u6708\u6642\uff0c\u5728<em>Science<\/em>\u767c\u8868\u4e86\u4e00\u7bc7\u6210\u529f\u7528\u5168\u75c5\u6bd2\u75ab\u82d7\uff0c\u4f86\u4fdd\u8b77\u975e\u4eba\u985e\u9748\u9577\u985e\u514d\u65bc\u81f4\u6b7b\u75c5\u6bd2\u5291\u91cf\u611f\u67d3\u7684\u7814\u7a76\u5831\u5c0e\u3002Kawaoka\u535a\u58eb\u5be6\u9a57\u5ba4\u5229\u7528\u7684\u75c5\u6bd2\u682a\u7f3a\u5931\u4e86\u91cd\u8981\u7684\u8f49\u9304\u6d3b\u5316\u86cb\u767dVP30\uff0c\u56e0\u6b64\u7121\u6cd5\u9032\u884c\u8907\u88fd\u3002\u9664\u6b64\u4e4b\u5916\uff0c\u4ed6\u5011\u9084\u5229\u7528\u904e\u6c27\u5316\u6c2b\u4f86\u9032\u4e00\u6b65\u6bba\u6b7b\u75c5\u6bd2\u3002\u9019\u500b\u53bb\u6d3b\u6027\u7684\u5168\u75c5\u6bd2\u75ab\u82d7\u4e26\u6c92\u6709\u5931\u53bb\u5b83\u7684\u6297\u539f\u6027\uff0c\u5728\u975e\u4eba\u985e\u9748\u9577\u985e\u7684\u5be6\u9a57\u88e1\uff0c\u6210\u529f\u7684\u523a\u6fc0\u514d\u75ab\u7cfb\u7d71\u7522\u751f\u4f0a\u6ce2\u62c9\u75c5\u6bd2\u62b5\u6297\u529b\u3002\u9019\u652f\u75ab\u82d7\u7684\u524d\u666f\uff0c\u4ee4\u4eba\u5341\u5206\u671f\u5f85\uff01<\/p>\n<p><strong>\u53c3\u8003\u8cc7\u6599\uff1a<\/strong><br \/>\n1. Marzi A, et al. Vaccines. An Ebola whole-virus vaccine is protective in nonhuman primates. <em>Science<\/em>. 2015 Apr 24;348(6233):439-42. doi: 10.1126\/science.aaa4919. Epub 2015 Mar 26.<br \/>\n2. Krause PR, et al. Immunology of protection from Ebola virus infection. <em>Sci Transl Med.<\/em> 2015 May 6;7(286):286ps11. Review.<br \/>\n3. Tully CM, et al. Emergency Ebola response: a new approach to the rapid design and development of vaccines against emerging diseases. <em>Lancet Infect Dis<\/em>. 2015 Mar;15(3):356-9. doi: 10.1016\/S1473-3099(14)71071-0.<\/p>\n<p><strong style=\"color: #000000;\"><span style=\"color: #333399;\">--<\/span><\/strong><br style=\"color: #000000;\" \/><strong style=\"color: #000000;\"><span style=\"color: #333399;\">\u4f5c\u8005\uff1a\u99f1\u5b9b\u7433\u3000\u7f8e\u570b\u8056\u8def\u6613\u83ef\u76db\u9813\u5927\u5b78\uff08Washington University in St. Louis\uff09\u514d\u75ab\u5b78\u535a\u58eb\uff0c\u5f9e\u4e8bT\u7d30\u80de\u767c\u80b2\u8207\u6d3b\u5316\u76f8\u95dc\u7684\u8a0a\u606f\u50b3\u5c0e\u7814\u7a76\u3002<\/span><\/strong><\/p>\n<p>&nbsp;<\/p>\n<p><a href=\"https:\/\/line.me\/R\/ti\/p\/%40fcx6182w\" target=\"_blank\" rel=\"noopener noreferrer\"><img decoding=\"async\" class=\"alignnone\" src=\"https:\/\/scdn.line-apps.com\/n\/line_add_friends\/btn\/zh-Hant.png\" alt=\"\u52a0\u5165\u597d\u53cb\" width=\"212\" height=\"36\" border=\"0\"><\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>\u25a0\u6240\u8b02\u9810\u9632\u52dd\u65bc\u6cbb\u7642\uff0c \u5982\u4eca\uff0c\u96e2\u7814\u767c\u51fa\u6709\u6548<\/p>\n","protected":false},"author":20,"featured_media":21762,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3293,1025],"tags":[1921,714,1573],"aioseo_notices":[],"jetpack_featured_media_url":"https:\/\/case.ntu.edu.tw\/blog\/wp-content\/uploads\/2015\/06\/vaccine.jpg","_links":{"self":[{"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=\/wp\/v2\/posts\/21761"}],"collection":[{"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=\/wp\/v2\/users\/20"}],"replies":[{"embeddable":true,"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=21761"}],"version-history":[{"count":5,"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=\/wp\/v2\/posts\/21761\/revisions"}],"predecessor-version":[{"id":32283,"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=\/wp\/v2\/posts\/21761\/revisions\/32283"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=\/wp\/v2\/media\/21762"}],"wp:attachment":[{"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=21761"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=21761"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/case.ntu.edu.tw\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=21761"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}