CINXE.COM

<!DOCTYPE html><html lang="en-US"><head><title>Just a moment...</title><meta http-equiv="Content-Type" content="text/html; charset=UTF-8"><meta http-equiv="X-UA-Compatible" content="IE=Edge"><meta name="robots" content="noindex,nofollow"><meta name="viewport" content="width=device-width,initial-scale=1"><style>*{box-sizing:border-box;margin:0;padding:0}html{line-height:1.15;-webkit-text-size-adjust:100%;color:#313131;font-family:system-ui,-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Helvetica Neue,Arial,Noto Sans,sans-serif,Apple Color Emoji,Segoe UI Emoji,Segoe UI Symbol,Noto Color Emoji}body{display:flex;flex-direction:column;height:100vh;min-height:100vh}.main-content{margin:8rem auto;max-width:60rem;padding-left:1.5rem}@media (width <= 720px){.main-content{margin-top:4rem}}.h2{font-size:1.5rem;font-weight:500;line-height:2.25rem}@media (width <= 720px){.h2{font-size:1.25rem;line-height:1.5rem}}#challenge-error-text{background-image:url(data:image/svg+xml;base64,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);background-repeat:no-repeat;background-size:contain;padding-left:34px}@media (prefers-color-scheme:dark){body{background-color:#222;color:#d9d9d9}}</style><meta http-equiv="refresh" content="390"></head><body class="no-js"><div class="main-wrapper" role="main"><div class="main-content"><noscript><div class="h2"><span id="challenge-error-text">Enable JavaScript and cookies to continue</span></div></noscript></div></div><script>(function(){window._cf_chl_opt={cvId: '3',cZone: "www.jbc.org",cType: 'managed',cRay: '8e6e25a93f513fa5',cH: 'XsyFu9nNVgqFT7LZ89r17IO52mmf6JZMfh9XPkSgdJY-1732333323-1.2.1.1-tRYzImhI6Gj4CFUyMSXMNUPmku7NZeXGPPWw8Imf2LVoIh88faqxsmCMCfkeqLGt',cUPMDTk: "\/article\/S0021-9258(19)57766-3\/fulltext?__cf_chl_tk=MC9KQwb5FmHtIdPxU.wkUX5XG_fZljY4VdLhJrq7OEo-1732333323-1.0.1.1-UczWYy9VaBEuuA32vzlI4_Q2bxan8HuLCSOQOz2iMxw",cFPWv: 'g',cITimeS: '1732333323',cTTimeMs: '1000',cMTimeMs: '390000',cTplC: 0,cTplV: 5,cTplB: 'cf',cK: "",fa: "\/article\/S0021-9258(19)57766-3\/fulltext?__cf_chl_f_tk=MC9KQwb5FmHtIdPxU.wkUX5XG_fZljY4VdLhJrq7OEo-1732333323-1.0.1.1-UczWYy9VaBEuuA32vzlI4_Q2bxan8HuLCSOQOz2iMxw",md: "rwT705_KFeB5EjqSbjgLACJyD1wMl2nureP4p3psXmI-1732333323-1.2.1.1-vjLQO.9otV6QeXx77MOmWHBSwqO64UzpiUpKe0GeX..hWDFvuAvt0U3Qg330DPvfoqhdqFP7X.41CyXMlTkxQyjs7yjbKAzsyAtGl8yKrN778uP0p8kJAWrqbHWG6VgFY.aXWukFcpqNc3hVSs0Tc_FqaX068iNWWqz_ntmASNirA4TLaUIPTwKCPW5I6cza8ZmOhtuRTYNBfkyGrfrohT0Zad9mQLIZpoMIbMUjDfW0Jn11L6yRDnDVZSCHbFk9Cv5vDtKckz_1w9YFo5GRaPPt9oljNmic96GtAMpqnFXT07CSFryXMQvPySGP0TswAmYhubw_XGCNFnP4wppwPe.uGvuLk4JdamkMcjqnJZ7f86w3sz_Qi97GBw7en50HfaGENpyolG6atEjw7awnDIkB_KrU.zyx_Pqa2hGslxyv3sSK4y2_PhyXbm1hAonuhMrGn8ulhUMZJ8RxmWbN8RF.8K3U7rwgkTtLuIKUwL_fWYGFcx0.0XfJuGxGvB1Fv4u7EDji7ykXQ8YgNdXlV0JYIbYYUGFfB9FquuOz0QaERh3no_4w9ZHzuxZf82P.WasJepWjTz6utNEOXEcHJndHLXhnV1nIBy5._0boY8y7zBN2WEjiiyTgPwrWBwmGNvlMQyOrHPeYcYPmtTlRmnYHWwVisGTmfGZ6zJxQ3Ka.Ag5Bh9dliRLQivMqi283lp2uzE73OIBk6Wm5DKu2lVc9BSuXOJ_ENDkpcYGPoTvGZaGuYUBunHupJXF7ZbEs9r1joynxFJ84afyKMJ7wiDAzudMvrsG2rHGp_Y.4b.2330ijCZa.Nu35UpNfBYjXnLKA.eGg.Jxh8gxO3nuzCER6C29M3Kq0JddbJ.Wo2wJoJWNBwglyagJ6nat53WQQzEHlOPBZMo_JbCTE0RCXq4afWSeiVB9FiunHUWcv2UiQsP0NYXq7nKe00yZHqP3fnM2xcKnn2vXH6Auu.qukXphomPs9TU7xRPSFJs08MYFj8GghQBfS_P1bzyrg_uUCll0HElDeBbukb2w82Y_KljW7d2Xlc2ncqF1zWdO9fTreIyGsXwknygVPKQIS3T2.1R2gu176PMaG_BI3HhkevQNzAId3RT2NWfYi3okJ4V8DKhbQNYw12CpabgI86KZ8AzUG1mMX3M2E99zDfnv8rhwYU9RDr9T9d5dHQrfFxIV3onx4h4ietIhu6cH4Ngcb3nADGVqZCpjBVZEHN2RmsSkfCymthFwsVOWPGsXX_kXDywWn3j83i1xbIv.8HawTKQQScivC0ho4gtfaV_yNV.lFnFOp3MR9Yd_byLn1kDwfYyMA_FKJzrQB5HwcI_M.HWvMgu7G_lmPFFycJaiz9tZi9iWCQOpV6kUjFDspyMb5k5ug3Fk_DUPyfMQ8NhDMX7fX.ZHsv1Puo2OQblUwvy7nSIYLpGCLzrJgAITYQe3osblfckDt6KIj2mZ97XxL1ky7ZrmKGBLTqiADaTSu_xOHJp_Bul.hQ4JU09NOtfsz1W7KFPW3yhM.Mz99PBU.LYNuWd3ahtgEt3cY.5kJOPbguwluYbaucjbvgF42A_g_BmDSbb0f7lilTVDbtOsKi0sDPeh261yv0YF0H0zOWZa22pcp.R10EAm29aTs_CPUtAloWc_AtZDntFCyjOzM.qIu1eK3n0xVGo9huXWkur5PIRHLQS5O2JE2r.IG6WlRRg0v99fgOs2_Xmf3OLE6TFlM9_tWD8.azclMi4vGjO8Bfq0HwfShD_kCuBmkzArkDkgfEeBzTOiczf0YSxIJtWB6J4oE_tQH1xiUDnAxxM5SFXWp3m10wmjEXCX8PQCxxKhKBkG1BL6mcvo6l6NSOOj2vdiJICNHH3sDZCm9itVbJVXHqddZs1FNQ0_ixOjhR96gNqncP3__ST0xCE0fBVG0NIgcH0o2Ml3b3hoFvKqiOcP9Vp9UtAi9Nyo27mrYx8aIFLSSAZH4A4rnEcOQnApXjb1n9d.XLVH4RH.5a9zUkHzJ1nZnOiwwqFDd0pkoAGl1leD_nFh6bkFPf7LQkR_DXicSky2lFE8kCHHdRT.ttDkjYMqB7F2Xs.fj267uhJLkRgvJrGnrJihofNHkAmevzjvLOPy5EpZdrdkYda0RZoPd5gNRx2.i0_p2zIM_YXWlmONc09UiJ0hkH.uqq6XKccoMvv_BoNvAbeqOe_2jW52cxdXW7BHdtu4PC80nDmfeS_gBX4XKZQ6TDdLkzRGTLI1auj9g6pVPat07_ypAT0pQSaNIu2WTOn4g7BWcW1hSdhimg2mPeWhiQWxwC0pBmwcv8FzlCO4kXVB6094qDTAlaRv191Zo5nLD6_.bGhYy1aPqlfK5_F8kcQLgdkapibBtjYbz1vxJVgnIbTYrWM_go7f0jHLkmOPlMkcaCDjfujpo0YWwuNCiv9PB_UGhgHVKQ0WhqFWUS2s6dtUmanjPkf4Kk06uPFHLPAcK0ksgo2I7m45DQ23z.QwZsjBAxJOVlvO.ddGhgbxRh4zE5WBXVn.LwTotuqmEW4KfJa5iDuJwjaUQRAWkavj4ba316NFSjaxCNAxpDUSWr3_BYk4XTsrGoT9O73VNZSvaDGLoEjbaq8ezRXxDolHJzNmkHZjnX2jWwYiCpTGBqQE3uYasStw7Aiyf3j.hypr2hA8UgS8zxHndNc4Vqk6m3mEZ5hbIHMs5y0HAD9uZqFzFHSr_vPTzH9aweoebI.atlvY2VA73FSD8AKOYSuI1VtYalbWG.2xyrXgpp1HxJ8hzjOf8DkOEJ_.pHrgUsFeoGlUkEftpdTNIbBbuTub5X1bkabFRaSewv3uUqw3bJ10gBxOnEEAmOICr.hcmzS.swt3QtT8qpDtY.S1YPafoxTntdwQKBcC1BzIF4XF4z4v.3.JAjsbHKdZmLYoaRSWMPAN2uv_6xYGnhCik65S8zocI75XTratXz.Q3_7Y33VzbSRvClA8bVLrKh0HjI.B.ZQBbCSCz4S4SoQnkOnE_",mdrd: "ivDjujgs4aGlOYK.80bBicbgLSKQQVhzJ2pFRJR8k6Q-1732333323-1.2.1.1-gALPVN2C1KkBhkpSXHRN69NMgkiwtr8G_nHK3UJx9U7mzbqfOAsDWgk086d4S4tiHe2hM8GEyCT6j1BRwES_i5wac4EAc67aXS_CpZJFyNpvEwQDUWeAn7zG5YCXqdcERIJq3dz0T1udC2GXrveXFd5Qty_qn8Aks5GASO7ie0oRRIL7V6gKhz1kr4IIt_.RT7eiAeSeLsqrbMZ5LpTGPFjONhjIYgVvV2VEybHsNHdmId_qQqTe6gkPWs0IiWANY9J1HFbAdUAuam2cStg6vyrGrMx8mnqyA5SdqDdbsESDnYsAYu6PTBxeLCthh3DjsbipSAGmUCbPfKP6XBkAR6ro6nz7LScf9rNSSsgw8jD9xP28ApoEy6mwp0Pehcj8p57eS4EC_DcHGSj4Bp8jLjD0AOL5kuAlGzobCSYkNE4BHdQCECX3vdDmHMywjtpPLV_n5o2yd0gP8nXC4tRCS52bCMv23sHwjvBoH10rYnezXjV7CiUytay2VEOeBmxdkSSk.DNLvYvhNuoOGCpgrtXYE5cMJXRMcF421dmCYL5pZV8PbmK_e6zyq.d1IpdHhgS.ysTFbV.ckNReFDdLuTw60M_jYvmRD_xsUhv6Artv_jjDerWqVHbQzlo.pJS.5fOuA9wnwZcdDR6.LrPNznTKw2HvACPfE33e5P222SxZU_Pt8O25z9Oy4ACh8J68jVXYSa6KvVMPAIaw7RZc7nDZhe_t23bHUP_gdtRuT1y3s93VQX3t6UyfeT43MwBOLWloaEAsc8ChKnpcdw_BsG8uIAxLa3MhgsESFL5Q.sNtYyYEYKslF3xCB_8QlGzJtjt8zRXrLTlpVeRdADiEB77Kpeobw.pIgMUH9hRPlXojo.J2GR_T7kawdES3Q9wDNHjO6a6qEDFUOCw.kTuAgV4kpoQH77RlcvOvuUfURbtZP_GKjpbhbMF0VYpwiUfCrZ1jBBBFa95rj5m.76h6f_LMejSOMUT1g9xRVO5yIDY8hAanJJM4nx8rZyn0RrfhvIhclWRPRnrbldpxyqnqnluHn9iXBlNfCkhOvg.MMnqNYU2ClZU8oxjWBQNYLz9husmcydiOVpmQpvufU3IHimBgB4lk7zf8jDSc._.gqRQgqs5yT4oi3aJdNhUUvtoZT_Kg9t2KIifboO_g3Tx2peuHk0jspGykfPjNz5sTuDsh_DpmwoSBzGUqA2_e.QKrDLOotn2T9XQpiPDDL5FSgek1gJhXjc7kw_G4dcgbdo7zAKa1VWlaImT_4JnYBfWz6Zbl_G2Zc6h5qYx8t2xzkcV83ANqpdqBL0Q4KzCFlRPET5jSiI78PJBSS9hHUXjjCEycqnxZKS_ZYdDhaNRMt9gOINgsq_U7a.9OQM6dM1JaC13KCCIeifRF_rLpMqxwVbMevd8SDFB8LTEgjzBw3X9J9P4KlCCoeZ.6_koOU7n_Dc6e.C5uCON3BXaLfZB5Y8dE0tfYJ_HcNjia0ULEt7dDho5noRWZIC6mQqKSzCmNT0wxomAbVKV02ULaX8Y197D4G1kUHgwH68Y_vncXCLIReGeuewKQfjlf8fCxM4gnIp1KpJJMhI4fB25ftSNvVOO8cLGBz.rJF69HIl42oXVs3wFXOQpUKUNbyRSGxZhxAeWB4GdYYSTVTLBjF_21vMRsKSO1aiD6hT1CvJGlO2bfL8mgh_uJtLVqKpiMPy6q8XsOP3XY45OXcGgabkA_8fGHLv0AekO4FPWpD2.Ver9bGLdaHLWrmSoA8ZrfyQF9E7Bu44nEsTNIBPtnbeLl0a2ONEPMDov0GZqAFnL6G8jdbcEvjf4_fVXz6qlXz0iv2lTjA_wsPb8WqO0iWA5Pd6zQBi6lVSV3HZZxpoQIwPMEitjVYaZAKX27xy1tOqOwVfg7YfR8XkUHjDk7.uYMq1Zk16JXfbdj9bPMjsNkbN4eGqa5ARzmRoRPS7ZapLI"};var cpo = document.createElement('script');cpo.src = '/cdn-cgi/challenge-platform/h/g/orchestrate/chl_page/v1?ray=8e6e25a93f513fa5';window._cf_chl_opt.cOgUHash = location.hash === '' && location.href.indexOf('#') !== -1 ? '#' : location.hash;window._cf_chl_opt.cOgUQuery = location.search === '' && location.href.slice(0, location.href.length - window._cf_chl_opt.cOgUHash.length).indexOf('?') !== -1 ? '?' : location.search;if (window.history && window.history.replaceState) {var ogU = location.pathname + window._cf_chl_opt.cOgUQuery + window._cf_chl_opt.cOgUHash;history.replaceState(null, null, "\/article\/S0021-9258(19)57766-3\/fulltext?__cf_chl_rt_tk=MC9KQwb5FmHtIdPxU.wkUX5XG_fZljY4VdLhJrq7OEo-1732333323-1.0.1.1-UczWYy9VaBEuuA32vzlI4_Q2bxan8HuLCSOQOz2iMxw" + window._cf_chl_opt.cOgUHash);cpo.onload = function() {history.replaceState(null, null, ogU);}}document.getElementsByTagName('head')[0].appendChild(cpo);}());</script></body></html>