Ɖuw̗jƐVȓWJ

<strong>{jE L</strong>
iww@wn Ɖuwj
emailF<a href="mailto:oka-im@m.u-tokyo.ac.jp">{j</a>C<a href="mailto:takayana@m.u-tokyo.ac.jp"> L</a>
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̈Zr[, <strong>1</strong>, e003 (2012)@<a href=" http://dx.doi.org/10.7875/leading.author.1.e003">DOI: 10.7875/leading.author.1.e003</a>
Kazuo Okamoto & Hiroshi Takayanagi: <strong>The history of osteoimmunology and its recent progress.</strong>

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<h2>v </h2>
@̍P퐫͍ӍזEłȂCق̑gDזEƂ̑ݍpGɐ䂳ĂDƂɁCƖƉun̓TCgJCȂǑ̐^pNLsȊ֌WzĂD֐߃E}`ɂ鉊ǐǰ͂ƖƉunƂ̑ݍpɌāC҂̗Z̈łgƉuwhW̌_@炵D܂CȖƉuǂɂďdvȃwp[TזẼTuZbgłTh17זÉC֐߃E}`ɂčjUjזEUTזEƂċ@\邱Ƃ炩ɂȂCƉuw̎_͗ՏɂĂdv𑝂ĂĂDɋߔNC\זEƑזEƂ̊֌WwECƉuw͑ʂɔWD

<h2>͂߂</h2>
@gD̍P퐫͍̌ÂgDĐVgDɒuւ邱ƁifOjɂێC͍זEɂ鍜`ƔjזEɂ鍜zƂ̃oXɂ萧䂳ĂD̃oX̔j]́C֐߃E}`Co㍜e頏ǁC񍜓]ڂȂǂ̍ʌ̎CdǁC嗝΍aȂǂЂNƂɂȂCЉނɂāCReBuVh[i^ǌQj͈̍Âɂ傫ȉۑłD̂悤ɍӍזE̘Agɂ萶UgDč\z킯CgD͂ق̑gDזEɂĂGɐĂD
@ȂłCƖƉun͍̔C܂CTCgJCVOi`BqȂǑ̐^pNLڂɊ֌WĂDgƉuwhiosteoimmunologyj͂ƖƉunƂ̑ݍpɃtH[JXZ̈ƂĔWĂ<a href="#R1"><sup>1)</sup></a>DgosteoimmunologyhƂď̂́C2000NCTזEɂjזE̐ɊւM҂̕񍐂̍ۂ<em>Nature</em>̘_LɂĎgpꂽƂɂ͂܂<a href="#R2"><sup>2)</sup></a>D܂ł̖͑ƉunTCgJCӂɂ邱Ƃ킩Ă邪CȂłRANKLireceptor activation of nuclear factor-B ligandj͍ƖƉunƂȂƂdvȃ^pNł<a href="#R3"><sup>3)</sup></a>DRANKLTזEɔזE̊^pNƂĖƉuwɂĂłɓ肳ĂTCgJCłD̂ɁCjזE̕ɂĕK{̃^pNł邱Ƃ𖾂C͖̔ƉunƍӂƂȂ傫Ȍ_@ɂȂD܂CjזE̕@𖾂ĂɂCӊOɂCƉun̍זEŋ@\鑽̃VOi`Bq]ʈqjזEɂƂĂdvł邱ƂCƖƉunɂ鋤L肢݂ɂȂD
@ł́C܂ł̍Ɖuw̔W̌o܂TC֐߃E}`̕aԂ̗ւނƉuw̌Cɂ́C̔ɂ鍜ƑזEjb`ɂĂ̍ŐV̒mЉC̊wۗ̈̐VWJɂďqׂD

<h2>1DƖƉunƂԃTCgJCRANKL </h2>
@jזE͒P/}Nt@[WnOזEɗR鑽jזEłCɐڒƋɐ_^pNyf𕪔傷邱ƂōzDjזE̕ɂ́CjזEOזEזE⊊ۉזEȂǊԗtn̎xזEƐڐGUVOi󂯎邱ƂKvłC1990N㔼ɁC̕ɕK{̃TCgJCƂRANKL肳ꂽDRANKL͔jזEOזEɂĎêłRANKƌUVOi`BDŋ߁CfOɂRANKL̔זEƂāCgDɖvזȄdv炩ɂꂽ<a href="#R4"><sup>4)</sup></a>D܂ŁC̒P̍̂ߍזE̐@\͕̌s\łCזEɂēٓIGFP𔭌`qσ}EX̍쐻ɂCזERANKLĂ邱ƂCɁCזEɂēٓIRANKL}EXł͔jזE̕Qɂ嗝΍a悷邱Ƃꂽ<a href="#R4"><sup>4)</sup></a>D
@RANKLmbNAEg}EXRANKmbNAEg}EX͏dĂȑ嗝΍aƎ̖GosS悷<a href="#R3"><sup>3)</sup></a>Dɏqׂ悤ɁCCRANKL͎זE𐧌䂷@\TCgJCƂĕ񍐂ꂽCRANKLmbNAEg}EXRANKmbNAEg}EXł͎זE̋@\ɍ͔F߂ȂDCRANKLmbNAEg}EXRANKmbNAEg}EXł̓p߂̌`sS⋹B̐זE̕QƂƉugDُ̈킪F߂DB̐זE̕ɂ͋BזE⃊pgDUזECTזERANKLVOi`B̕Kv_Ă<a href="#R5"><sup>5,6)</sup></a>CƉue̐ɂRANKL-RANKoHĂD܂C\זEɗRRANKL䐫TזȆBUCAM[ڐG畆⎩ȖƉu畆̗}ɂ͂炭Ƃ񍐂<a href="#R7"><sup>7)</sup></a>Dɍŋ߁C䐫TזEYRANKL͓̓]ڂɂƂ񍐂ȂĂ<a href="#R8"><sup>8)</sup></a>CRANKL͍Ɍ肳ꂸƉunɂĂɑʂȋ@\D

<h2>2DjזE̕̕q@\</h2>
@1990N㖖܂ŁC嗝΍a}EX悷NF-B p50NF-B p52̃_umbNAEg}EXCc-FosmbNAEg}EXCTRAF6mbNAEg}EX̉͂ɂCjזE̕ɂ邱̃^pN̏dv炩ɂĂ<a href="#R1"><sup>1)</sup></a>DC̓C^[CL1TolllêȂǔjזE̕UȂ悤Ȏhł^pNłCRANKLhɑ΂ٓIȃVOi`BqƂ͂ȂDM҂́CjזEpԗIȃgXNvg[͂ɂCRANKLhɂٓIɗU]ʈqƂNFATc1inuclear factor of activated T cell c1joCNFATc1jזE̕ɂ}X^[]ʈqł邱Ƃ𖾂炩ɂ<a href="#R9"><sup>9,10)</sup></a>DNFATc1͕̉ߒŋNÃ_Ci~bNȌ`ԕω⍜z̋@\ɂ`q̔U邱ƂłCjזE̕ɂ钆Iȋ@\SDŏCNFATt@~[TזE̊ɂƂē肳ꂽ]ʈqłC̔ɂĂCƖƉunƂ̋ʍڂoꂽD
@̂̂CITAMiimmuno-receptor tyrosine-based activation moitifjzITAMA_v^[^pNłDAP12iDNAX-activating protein 12jFce̋ʃTujbgƉƉuOulêCNFATc1̗UƊɕK{Ca<sup>2+</sup>VOiN鋤hêł邱<a href="#R11"><sup>11)</sup></a>CɁCTecBtkRANKITAMA_v^[^pNƉuễVOi̓ɕK{ł邱Ƃ𖾂炩ɂ<a href="#R12"><sup>12)</sup></a>i<a href="#F1">}1</a>jDہCDAP12Fce̋ʃTujbgƂ̃_umbNAEg}EXCBtkTecƂ̃_umbNAEg}EXł͔jזȄ̕QŏdĂȑ嗝΍a悷DMׂ_́CA̔jזE̐^pNƉunƋLĂ邱ƂłDقɂCSHP-1SHIPȂǂ̒E_yfCBlimp1CIRF8CBcl6ƂƉunɂďdvȖS^pNjזE̕ɂ邱ƂoĂ<a href="#R1"><sup>1)</sup></a>D

<a name="F1"></a><div id="fig1-caption-text" style="display: none;"><strong>}1@RANKLhɂUjזE̕VOiNFATc1ɂ鐧@\</strong>
RANKLhɂƂTRAF6CNF-BJNKȂǂDITAMA_v^[^pNiFce̋ʃTujbgCDAP12jƉƉuOuléiOSCARCPIR-ACTREM-2CSIRP1j́CCa<sup>2+</sup>VOi̗UɕK{̋hêƂċ@\邪C̃KhɊւĂ͂܂sȓ_D܂CZ}tH6D̓vLVA1-TREM-2-DAP12̂ĔjזE̕𐳂ɐ䂷CZ}tH3A̓vLVA1-TREM-2-DAP12̂̌`jQjזE̕𕉂ɐ䂷DBtkTecRANKVOiɂ芈CBLNKSLP76ƉăzXzp[[C̃_ЂNĎʁCזECa<sup>2+</sup>Zx㏸CJVj[NFATc1̊юȑUD܂CJWLi[[IVCCREBc-FosUNFATc1̓]ʊ\𑣐iDNFATc1̓JevVKCTRAPCJVgjéCOSCARCDC-STAMPƂjזE̕ы@\ɂ`q̔UD
FcRFFce̋ʃTujbgCPLCFzXzp[[CCCaMKIVFJWLi[[IVD
<a href="http://leading.lifesciencedb.jp/wordpress/wp-content/uploads/2012/08/Takayanagi-1.e003-Fig.1.jpg" target="_blank">[Download]</a></div>[hs_figure id=1&amp;image=/wordpress/wp-content/uploads/2012/08/Takayanagi-1.e003-Fig.1.png&amp;caption=fig1-caption-text]


<h2>3DhVOijזE̕</h2>
@Fce̋ʃTujbgƉƉuOulêƂPIR-Aipaired immunoglobulin-like receptor-AjOSCARiosteoclast-associated receptorjCDAP12ƉƉuOulêƂTREM-2itriggering receptor expressed in myeloid cells-2jSIRP1isignal-regulatory protein 1j肳Ă<a href="#R11"><sup>11)</sup></a>D܂C<em>DAP12</em>`q<em>TREM-2</em>`q̋@\rψق́CXEɂaIȍ܂Ɣ]ǂɂNFmǂ咥ƂNasu-Hakolaa̐Ƃē肳ĂD}EXɂ鍜̕\^Nasu-Hakolaa҂ł݂鍜̏Ǐ͊SɈvȂC҂ɗR閖Pjł͔jזE̕ɏQF߂_CjזE̕ɂ鋤hVOȉdvłD
@ߔNC_o̔⏉̔ɂvLVA1CjזEɂTREM-2DAP12ɉZ}tH6DVOi`B邱ƂŔjזE̋@\Ɋ֗^Ă邱Ƃ񍐂ꂽ<a href="#R13"><sup>13)</sup></a>i<a href="#F1">}1</a>jDہCvLVA1mbNAEg}EX͔jזE̕Qɂ嗝΍a悵CvLVA1-TREM-2-DAP12̂@\jזE̕ɂďdvł邱Ƃ킩Dɍŋ߁C̃vLVA1-TREM-2-DAP12̂ɂ镪ɊւĐVȐ@\炩ƂȂDjזEOזEł͍זE̎YZ}tH3Aɂj[s1ƃvLVA1ȂZ}tH3Aê̕`CvLVA1-TREM-2-DAP12̂̌`jQĔjזE̕}DȂCj[s1̔RANKLhɂ蒘ɒጸ邽߁CRANKLĥ̂ɂ̓vLVA1-TREM-2-DAP12̂`Z}tH6DVOi`Bł悤ɂȂ<a href="#R14"><sup>14)</sup></a>i<a href="#F1">}1</a>jD[ƂɁCZ}tH3A͌ÓTIWntoHčזE̕𑣐iCbזE̕}@\ƂDȂ킿Cz̗}ƍ`̑iƂd̍pƂCZ}tH3A֘A̐VK̎ÖƂȂ邱Ƃ҂D

<h2>4D֐߃E}`ɂ鍜jTh17זE</h2>
@֐߃E}`ɂ鍜j͍ƖƉun̖ڂȊ֌WƂڂƂȂaԂłD֐߃E}`̔Ǐ̊ɂĂTזEȂǂ̉ǐזE̐ZF߂Cł͎ᇗlɑBgDipkXj̓ɐN鑜F߂DgDɂTזECۉזEC}Nt@[WȂǂ݂CC^[CL6CC^[CL1CTNFȂǂ̉ǐTCgJC^pNyfʂɎYĂDɁC֐ߔjaɂ͑̔jזEώ@CjזĚ}EXȂтɔjזE̋@\Qꂽ}EXɎIɊ֐߉UĂj󂪔F߂ȂƂCjזE͉ǐjɂďdvł邱Ƃ؂Ă<a href="#R15"><sup>15)</sup></a>D
@ȖƉu̒ƂȂTזEɊւāCjƂ̊֌W͒Nɂ킽słDTזEꎩ̂RANKL𔭌ړIɔjזE̕𑣐iƂ񍐂<a href="#R16"><sup>16)</sup></a>Ĉ̕M҂̉͂ɂCȊTזE͑ʂɎYC^[tF̍pɂjזE̕jQ邱Ƃ킩<a href="#R2"><sup>2)</sup></a>i̕񍐂āCɂqׂ悤ɁC<em>Nature</em>̘_LɂāgosteoimmunologyhƂt܂ꂽjDCD4zTזE͍Rhɂ芈ƁC͂̃TCgJC̊ɂقȂwp[TזETuZbgւƕDTh1זE͂ɃC^[tFYC}Nt@[W̊ȂǂĉǉUזEɐN׋ۂ̔rɂD܂CTh2זE̓C^[CL4C^[CL13ȂǂYC񐶒ɑ΂銴hAM[ɂDċߔNCVK̃TuZbgƂē肳ꂽTh17זE̓C^[CL17C^[CL22YCȖƉủǂזEO̍׋ۂ邢͐^ۂ̊ɑ΂hɕKvƂĂ<a href="#R17"><sup>17)</sup></a>D
@݂ł͂ꂼ̃wp[TזETuZbg̐Ɋւ[܂̂́CM҂炪jזEUTזE̓Ɏg݂͂߂́C܂Th1/Th2p_CɂƉuaԂĂł֐߃E}`Th1^̎łƍlĂDŎۂɁCꂼ̃wp[TזETuZbgjזE̕֋yڂʂʂɌƂCTh1זETh2זE͂ƂɔjזE̕}CꂼC^[tFуC^[CL4ȗ}qł邱ƂDCC肳ꂽ΂Th17זEɂČƂCTh17זE͍זEƍזEƂ̋|{nɂĔjזE̕ɗUł邱ƂmFꂽD܂CC^[CL17mbNAEg}EXɗRTh17זEł͂̔jזE̕U\͒ႩDC^[CL17͊זEɂRANKL̔U銈ĂCTh17זE̓C^[CL17̎YčזEɂRANKL̔U邱Ƃ炩ɂȂ<a href="#R18"><sup>18)</sup></a>DTh17זÉC1jǏ̉ǂNC2jC^[CL17Ǐ̉ǂ̎Nɂ芊ۉזEɂRANKLUC3jTh17זEꎩ̂RANKL𔭌CƂCjזEUTזETuZbgƂčjɂ邱Ƃ炩ɂȂi<a href="#F2">}2</a>jD

<a name="F2"></a><div id="fig2-caption-text" style="display: none;"><strong>}2@Th17זEɂ鉊ǐj̋@\</strong>
֐߂̊ɐZTh17זÉCC^[CL17Y邱ƂŊ}Nt@[WCǐTCgJCiC^[CL1CC^[CL6CTNFj̎Y𑣂DC^[CL17͂ꎩ̂ۉזEɍpRANKL̔U邱ƂłD܂CǐTCgJCRANKLU\ĎʁCRANKL̔ɂƂȂjזE̕iCߏȍj󂪐D
ILFC^[CLCIFNFC^[tFD
<a href="http://leading.lifesciencedb.jp/wordpress/wp-content/uploads/2012/08/Takayanagi-1.e003-Fig.2.jpg" target="_blank">[Download]</a></div>[hs_figure id=2&amp;image=/wordpress/wp-content/uploads/2012/08/Takayanagi-1.e003-Fig.2.png&amp;caption=fig2-caption-text]


<h2>5D֐߃E}`ɂ鉊ǐj̎Ð헪</h2>
@xRE}`͉ǂ̗}ʂwWɊJĂCM҂́CggLT[gCtm~hCT]Xt@sWCuV~C^NXȂǂRANKLVOi̗}RANKL̗}ʂƂ<a href="#R19"><sup>19)</sup></a>i<a href="#F3">}3</a>jDTNFɑ΂钆aR̂nê͗ՏɂĂƂтwIȐ܂łCłɉǂɑ΂錰ȗ}\łȂCjɂʂƂ؂Ă<a href="#R15"><sup>15)</sup></a>D܂C{̐܂łRIL-6e̍RtocilizumabA̗Տ֐ߔjɑ΂鋭}ʂF߂ĂDRIL-6e̍R̂TNFjQÖ@ƓlɔjOזE╪xזEւ̍p҂C܂CTh17זȆjQƂȖƉuǂ̏㗬ɍp\Dŋ߁CTh17זE̎YC^[CL17ǂ̋ǏɂăC^[CL6̎YЂNƂ֐߉̕aԂɏdvłƕ񍐂<a href="#R20"><sup>20)</sup></a>CTh17זẼGtFN^[@\jQʂ҂łD2010NɍF󂯂CTLA4-IgiabataceptjɊւĂCTNFjQÖ@ɂ͗̂́Cj̗}ʂ͗Տxɂĕ񍐂ĂC̈S̍]ĂDɁCRIL-17ŔiLY2439821CsecukinumabjCRC^[CL12/23 p40ŔiustekinumabCbriakinumabjCRC^[CL23 p19R̂ƂTh17זE^[QbgƂ鐶wIȐ܂̊Jł<a href="#R15"><sup>15)</sup></a>DRIL-17R̂̊֐߃E}`ɑ΂IǏʂł́CTNFjQÖ@C^[CL6jQÖ@܂ł͂ʂ̂́CƂLY2439821ɂėLӂȌʂC܂CRIL-C^[CL12/23 p40Rustekinumab͊ᝂɑ΂łɏFĂ邪֐߃E}`ɑ΂Ă͎łC̉͂҂<a href="#R21"><sup>21)</sup></a>DCTCgJCểɂ`VLi[[JAKWIƂjQJĂCȂłCtofacitinib͐wIȐ܂ɔ䌨ƂՏ񍐂Ȃ꒍ڂ܂Ă<a href="#R22"><sup>22)</sup></a>D

<a name="F3"></a><div id="fig3-caption-text" style="display: none;"><strong>}3@֐߃E}`ɂ鉊ǐj̎Ð헪</strong>
֐߃E}`ɂẮCזEȂǂ̍R񎦍זEȍR񎦂CD4zTזECȖƉuNDɁCC^[CL6C^[CL23̍pɂTh17זE̕UCjזEُɊꍜj󂪐isDǏ̉ǂ̒SIȃfBG[^[ƂĂ͂炭ǐTCgJCłTNFC^[CL6ɑ΂鐶wIȐ܁CсCCD28CD80邢CD86Ƃ̌ɍpTזE̗̊}ɂ͂炭CTLA4-IǵCłɊ֐߃E}`̗ՏɂčLgpʂ𔭊ĂD܂CxRE}`͑ʂȍp@CjזẺ̕ߒɂpčj̗}pD܂CRC^[CL23R̂RORtjQ܂Th17זE̗U}CRC^[CL17R̂Th17זẼGtFN^[@\jQ邱Ƃ҂DJevVKjQ܂͉ǂƍjƂ𓯎ɎÂ鑊ʂ҂łD
ILFC^[CLD
<a href="http://leading.lifesciencedb.jp/wordpress/wp-content/uploads/2012/08/Takayanagi-1.e003-Fig.3.jpg" target="_blank">[Download]</a></div>[hs_figure id=3&amp;image=/wordpress/wp-content/uploads/2012/08/Takayanagi-1.e003-Fig.3.png&amp;caption=fig3-caption-text]

@Th17זE̕ɂ̓I[t@jêłRORtiretinoid-related orphan receptor tjK{ł邱ƂmĂ<a href="#R17"><sup>17)</sup></a>Dŋ߁CRORtɑ΂ٓIȑjQ܂oC}EX̑dǃfɍʂƂ񍐂ꂽ<a href="#R23"><sup>23,24)</sup></a>D܂M҂́C]ʈqIBĂTh17זE̕ɂVK̐^pNł邱ƂoCTh17זE̕ɓ]ʈqIBĂRORtƂ̋pKvł邱Ƃ𖾂炩ɂĂ<a href="#R25"><sup>25)</sup></a>DTh17זE̕ɂ]ʐ̌͐VK̎Ö@̊JɂȂ\߂ĂCEŐ͓IɍsĂDJevVK͔jזEɂ鍜zɏdvȃveA[[łCʌ̎ɑ΂L]ȎÕWIłDM҂́CVK̃JevVKjQ܂JC̒ᕪq̑jQ܂jזE̍z}e頏ǃf֐߉fɍʂƂ𖾂炩ɂ<a href="#R26"><sup>26)</sup></a>D[ƂɁCJevVK͎זEɂTolllê̂ЂƂTLR9̃VOi̐ɂ͂炫CTh17זE̕Uɂ邱Ƃ킩DāCJevVKjQ܂͊֐߃E}`ɂĐNƉunƍƂ𓯎ɎÂłƂʂ҂łi<a href="#F3">}3</a>jDqgƃ}EXłTh17זE̕ɕK{̃TCgJCقȂĂƂ񍐂<a href="#R17"><sup>17)</sup></a>CCaԂ⎡×lŁC֐߃E}`ɂTh17זE̐⓮ԂɊւڍׂȉ͂Kvł낤D

<h2>6Dɂ鍜ӍזEƑזE</h2>
@ߔNCזEjזEƂӍזE̔ɂđזËێ⓮ɂƂ[񍐂D2003NCזȆƑזE̍זEƂ̑֐񍐂CgזEjb`hꂽ<a href="#R27"><sup>27,28)</sup></a>D̂̂CזE̐@\̗}ꂽ`qσ}EX̉͂ɂĕ̕񍐂̂́Cꂵʂ͓ĂȂ<a href="#R29"><sup>29)</sup></a>D܂C̕񍐂łN-JhwzזȄdvwEĂ邪CN-Jhw}EXłזE̐͐łƂ񍐂ȂĂCזEjb`̏dvɊւĂ͋c_ĂDזEjb`ɊւẮCCARזEiCXCL12𔭌ȍזԍזEj⌌ǓזEClX`zԗtnזEƂ̍\זȄdv񏥂Ă<a href="#R29"><sup>29)</sup></a>D܂CɂBזȄɂĂCARזE⍜זECזE̊֗^Ă<a href="#R30"><sup>30-32)</sup></a>C̕G_Ԃ݂DƂɁCCARזEуlX`zԗtnזE͍זEւ̕\Ƃ񍐂ĂĆC̍זEɂ֌W𖾊mɂ邱Ƃۑł낤D܂CjזEJevVK}gbNX^veA[[̂ЂƂMMP-9̕CXCL12𕪉CזE̖zւ̗̓UɂƂ񍐂<a href="#R33"><sup>33)</sup></a>Dŋ߁Cc-FosmbNAEg}EX<em>op</em>/<em>op</em>}EXƂjזE}EX̉͂ɂC̓̐\ɊւĔےIȌȂĂ<a href="#R34"><sup>34)</sup></a>D

<h2></h2>
@Z}tH6DZ}tH3ÂقɂCjזEɂYZ}tH4DזE̕𐧌䂷ƂCjזEƍזEƂ̐VȑݍpoĂ<a href="#R35"><sup>35)</sup></a>DƉun̐䂾łȂ_oȞ`ɂdvȃZ}tHt@~[^pN܂܂ȋǖʂɂčӂ𐧌䂵ĂƂ̔ɂCƉuwƂ͕ʂ̕Ƃ̗Z҂D܂Cł́CƖƉunƂ\IȕaԂƂĊ֐߃E}`ЉCقɂo㍜e頏ǂ≊ǐ܂Ȃǂ܂܂Ȏ݂DC֐߃E}`łȂՏւ̍vɂȂ炢Cق̎̐ɂĂƉuwdvȒm񋟂CՏp֋nł邱Ƃ]܂D

<h2> </h2>
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</ol>
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