更新于：2024-11-05

Ezobresib

更新于：2024-11-05

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名

(S)-2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol、2-(3-(3,5-Dimethyltriazol-4-yl)-5-((S)-oxan-4-yl(phenyl)methyl)pyrido(3,2-b)indol-7-yl)propan-2-ol、BMS 986158

+ [1]

靶点

BET

作用机制

BET抑制剂(溴结构域和超末端结构蛋白家族抑制剂)

治疗领域

肿瘤血液及淋巴系统疾病免疫系统疾病+ [2]

在研适应症

血液肿瘤浆细胞骨髓瘤难治复发性多发性骨髓瘤+ [2]

非在研适应症

晚期癌症晚期恶性实体瘤

原研机构

Bristol Myers Squibb Co.

在研机构

Bristol Myers Squibb Co.

中美上海施贵宝制药有限公司

非在研机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (欧盟)

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结构

分子式C30H33N5O2

InChIKeyKGERZPVQIRYWRK-GDLZYMKVSA-N

CAS号1800340-40-2

关联

项与 Ezobresib 相关的临床试验

NCT05372354 / Recruiting临床1/2期

An Exploratory Phase 1b/2a Multicenter, Open-Label, Novel-Novel Combination Study to Assess the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of CC-92480 (BMS-986348) in Novel Therapeutic Combinations in Participants With Relapsed or Refractory Multiple Myeloma

The purpose of this study is to assess the safety, tolerability and preliminary effectiveness of CC-92480 (BMS-986348) in novel therapeutic combinations for the treatment of Relapsed or Refractory Multiple Myeloma (RRMM).

开始日期2022-10-18

申办/合作机构

Bristol Myers Squibb Co.

CTIS2023-509635-89-00 / Not yet recruiting

A Phase 1b/2 Study of BMS-986158 Monotherapy and in Combination with Either Ruxolitinib or Fedratinib in Participants with DIPSS-Intermediate or High Risk Myelofibrosis - CA011-023

开始日期2021-12-23

申办/合作机构

Bristol-Myers Squibb International Corp.

NCT04817007 / Active, not recruiting临床1/2期

A Phase 1b/2 Study of BMS-986158 Monotherapy and in Combination With Either Ruxolitinib or Fedratinib in Participants With DIPSS-Intermediate or High Risk Myelofibrosis

The purpose of this study is to assess the safety, tolerability, and efficacy of BMS-986158 alone and in combination with either Ruxolitinib or Fedratinib in participants with Dynamic International Prognostic Scoring System (DIPSS)-intermediate or high risk blood cancer. Part 1 consists of BMS-986158 in combination with either Ruxolitinib or Fedratinib and Part 2 consists of BMS-986158 in combination with either Ruxolitinib or Fedratinib and BMS-986158 alone.

开始日期2021-03-22

申办/合作机构

Bristol Myers Squibb Co.

100 项与 Ezobresib 相关的临床结果

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100 项与 Ezobresib 相关的转化医学

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100 项与 Ezobresib 相关的专利（医药）

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项与 Ezobresib 相关的文献（医药）

2023-10-20·Science advances

In vivo neuromodulation of animal behavior with organic semiconducting oligomers

Article

作者: Tortiglione, Claudia ; Stavrinidou, Eleni ; Dufil, Gwennaël ; De Simone, Mariarosaria ; Iencharelli, Marika ; Santillo, Silvia ; Tommasini, Giuseppina ; Tino, Angela ; Mantione, Daniele

Modulating neural activity with electrical or chemical stimulus can be used for fundamental and applied research. Typically, neuronal stimulation is performed with intracellular and extracellular electrodes that deliver brief electrical pulses to neurons. However, alternative wireless methodologies based on functional materials may allow clinical translation of technologies to modulate neuronal function. Here, we show that the organic semiconducting oligomer 4-[2-{2,5-bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)thiophen-3-yl}ethoxy]butane-1-sulfonate (ETE-S) induces precise behaviors in the small invertebrate Hydra , which were dissected through pharmacological and electrophysiological approaches. ETE-S–induced behavioral response relies on the presence of head neurons and calcium ions and is prevented by drugs targeting ionotropic channels and muscle contraction. Moreover, ETE-S affects Hydra ’s electrical activity enhancing the contraction burst frequency. The unexpected neuromodulatory function played by this conjugated oligomer on a simple nerve net opens intriguing research possibilities on fundamental chemical and physical phenomena behind organic bioelectronic interfaces for neuromodulation and on alternative methods that could catalyze a wide expansion of this rising technology for clinical applications.

2023-08-01·Molecular cancer therapeutics

Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma.

Article

作者: Bajwa, Amandeep ; Fang, Jie ; Shibata, David ; Bisunke, Bijay ; Rana, Manjul ; Glazer, Evan S ; Yang, Jun ; Kansal, Rita G

Identifying novel, unique, and personalized molecular targets for patients with pancreatic ductal adenocarcinoma (PDAC) remains the greatest challenge in altering the biology of fatal tumors. Bromo- and extra-terminal domain (BET) proteins are activated in a noncanonical fashion by TGFβ, a ubiquitous cytokine in the PDAC tumor microenvironment (TME). We hypothesized that BET inhibitors (BETi) represent a new class of drugs that attack PDAC tumors via a novel mechanism. Using a combination of patient and syngeneic murine models, we investigated the effects of the BETi drug BMS-986158 on cellular proliferation, organoid growth, cell-cycle progression, and mitochondrial metabolic disruption. These were investigated independently and in combination with standard cytotoxic chemotherapy (gemcitabine + paclitaxel [GemPTX]). BMS-986158 reduced cell viability and proliferation across multiple PDAC cell lines in a dose-dependent manner, even more so in combination with cytotoxic chemotherapy (P < 0.0001). We found that BMS-986158 reduced both human and murine PDAC organoid growth (P < 0.001), with associated perturbations in the cell cycle leading to cell-cycle arrest. BMS-986158 disrupts normal cancer-dependent mitochondrial function, leading to aberrant mitochondrial metabolism and stress via dysfunctional cellular respiration, proton leakage, and ATP production. We demonstrated mechanistic and functional data that BETi induces metabolic mitochondrial dysfunction, abrogating PDAC progression and proliferation, alone and in combination with systemic cytotoxic chemotherapies. This novel approach improves the therapeutic window in patients with PDAC and offers another treatment approach distinct from cytotoxic chemotherapy that targets cancer cell bioenergetics.

2023-07-03·Natural product research3区 · 化学

A new δ-valerolactone produced by marineStreptomycessp. YIM 13591

3区 · 化学

Article

作者: Zhang, Bing ; Zhao, Qing ; Zhang, Xiao-mei ; Zhao, Yu-ying ; Huang, Zhi-pu ; Xu, Xiao-rong ; Zhang, Ke-tao

A new δ-valerolactone compound, named 8-hydroxy invictolide 2 (1), a new natural product 4-hydroxy-3,5-dimethyl-6-(pentan-2-yl) tetrahydro-2H-pyran-2-one (2) together with four known compounds cyclo (L-Pro-L-Tyr) (3), cyclo (D-Pro-L-Tyr) (4), acetyltryptophan methyl ester (5), 2-aminobenzoic acid (6) were isolated from marine Streptomyces sp. YIM 13591. Their structures were elucidated by NMR spectroscopic data, HRESIMS and specific rotation, and the absolute configurations of the stereo centre in lactone ring 1 and 2 were further confirmed by electronic circular dichroism (ECD) calculation. The antimicrobial effects of these compounds were evaluated by the paper diffusion method.

项与 Ezobresib 相关的新闻（医药）

2024-04-25

·Firstwordpharma

BMS to cut 2200 jobs, trim pipeline in effort to be more ‘agile’

Bristol Myers Squibb on Thursday said that around 2200 staff will be impacted by cost-cutting measures that are designed to save about $1.5 billion by the end of 2025, with two-thirds of the savings coming from R&D. The company noted that the initiative includes a reduction in management layers in an effort to speed decision making, along with pipeline rationalisation and site consolidation.CEO Christopher Boerner, who took over as CEO from Giovanni Caforio at the end of last year, indicated that the “strategic productivity initiative…will allow us to be more agile…and prioritise investing in opportunities where we see the greatest potential." Meanwhile, chief financial officer David Elkins noted that the “vast majority” of the cost savings will come from Bristol Myers Squibb’s legacy operations, rather than from the integration of recent acquisitions.12 programmes discontinuedThe company said that in terms of its pipeline, it will focus on assets and programmes that offer a higher return on investment. Chief medical officer Samit Hirawat noted that around 12 programmes have so far been discontinued or earmarked for externalisation, including its efforts in CTLA4 beyond Yervoy. “We had set the bar with” Yervoy, Hirawat remarked, adding “we decided that if the data are not going to be better…we shouldn't be continuing that programme.” The executive noted that the same was true for its anti-SIRPα asset, which “did not meet muster,” while the market size for the experimental BET inhibitor BMS-986158 in myelofibrosis meant it would not be a growth driver.“The data are pretty good…but really from our perspective [BMS-986158] does not meet the threshold to be [a] driver for our growth potential. So that programme we are not going to be continuing,” Hirawat explained. “Throughout the year, we'll continue to look at these same principles and see what else we need to take out from our pipeline. And either externalise it or not be able to develop it further,” Hirawat said.Cuts already under wayBristol Myers Squibb started cutting jobs earlier this year amid plans to terminate a total of 423 employees in San Diego following its $4.8-billion acquisition of Mirati Therapeutics. The company has also recently completed the purchases of Karuna Therapeutics for $14 billion and RayzeBio for $4.1 billion, with associated costs hitting profit in the first quarter. Bristol Myers Squibb posted a loss of $11.9 billion in the three-month period, versus a profit of $2.3 billion in the prior year. Meanwhile, sales rose 5% to $11.9 billion, topping forecasts of $11.5 billion, with growth led by new drugs such as Reblozyl (+72% to $354 million) and Opdualag (+76% to $206 million), as well as older medicine Eliquis (+9% to $3.7 billion). However, revenue from Opdivo fell 6% to $2.1 billion.Chief commercialisation officer Adam Lenkowsky explained that Opdivo was hit by changes in buying patterns in the US, but the company is "confident we will see accelerating growth this year."Bristol Myers Squibb reiterated its sales outlook for the year of low-single-digit growth, but cut its earnings guidance to now include the acquisitions of Karuna and RayzeBio. The drugmaker expects earnings per share of between $0.40 and $0.70, revised down from the earlier range of $7.10 to $7.40 per share.

并购财报高管变更IPO

2023-12-05

·药智网

眨眼之间，吸金160亿的AOC药物

近日，BMS与Avidity达成全球许可和研究合作协议，利用Avidity的平台技术，专注多达5个心血管抗体-寡核苷酸偶联(AOC)药物靶点的发现、开发和商业化。根据协议，Avidity将获得1亿美元预付款，其中含6000万美元现金支付，及按每股7.88美元购买约4000万美元的Avidity普通股，此外，还有高达13.5亿美元的研发里程碑，和高达8.25亿美元的商业里程碑付款等等，BMS潜在累计付款23亿美元（约合人民币160亿元）。与“魔法子弹”ADC一个字母之差的AOC，眨眼间身价暴涨。01AOC的价值，远不止160亿元一切皆可联，越联越值钱。ADC的成功,让越来越多的“对象”进入到偶联“配对”范围，AOC就是其中之一。通过将单抗和寡核苷酸偶联，达到有效的靶向治疗能力，相比寡核苷酸，具有精准靶向和更好药代动力学特性，其结构与ADC相似，主要由发挥组织靶向作用载体（抗体）、连接子（linker）和治疗载荷（小核酸）等三部分构成。图1 AOC结构图片来源：美迪西官微全球首款进入临床的AOC药物AOC 1001就来自Avidity，除AOC 1001之外，Avidity还有2款AOC候选药已进入临床阶段，分别为AOC 1044和AOC 1020。Avidity在开发AOC项目时，结合3种不同罕见病进行研发，即AOC 1001用于治疗1型肌强直性营养不良症(DM1)，AOC 1044用于治疗杜氏肌营养不良症(DMD)，AOC 1020用于治疗面肩肱肌营养不良症(FSHD)。图2 Avidity研发管线图片来源：Avidity官网目前，全球并无AOC药物获批，据不完全统计，全球进入临床阶段（含IND申请）超过5款，最早“出线”的AOC 1001目前最高也只推进至2期临床，就算临床进展一切顺利，离获批上市也还较遥远，但BMS不仅愿意花160亿元，且还愿意承担所有未来临床开发、监管和商业化活动的资金，这就已让双方合作的AOC项目价值远超160亿元。AOC到底有何魅力，让BMS不惜花重金拿下？可以从其临床数据窥探一二。作为首个临床的AOC项目，AOC 1001的研究数据也是最先出炉。2023年4月，Avidity在第75届美国神经病学学会(AAN)年会上，公布了1/2期MARINA试验顶线数据，显示DM1患者各种功能评估有方向性改善，包括6个月期间的肌强直和肌肉力量，且具有良好安全性和耐受性。美国FDA在5月就放宽了部分临床限制，允许12名参与者将剂量升至4mg/kg，并允许新参与者以2mg/kg入组。图3 AOC 1001 1/2期MARINA试验不良事件图片来源：Avidity官网2023年10月，Avidity在第28届世界肌肉协会(WMS)年度大会上，公布了AOC 1001新的数据，增强了先前报道的肌强直、肌肉力量和活动能力改善的积极数据，且超过200次输注，总计46.2患者年的暴露数据，继续显示出良好安全性和耐受性，大多数不良事件为轻度至中度。图4 AOC 1001 4mg/kg临床疗效图片来源：Avidity官网越来越好的临床试验数据，让AOC在偶联药圈中，继ADC之后脱颖而出。02重押AOC，只为应对GLP-1？心血管领域是BMS支撑业绩的最重要“阵地”，仅抗凝血药物Eliquis在2022年的销售额就达117.89亿美元，比BMS的O药还高出42.91%，占全年总营收（461.59亿美元）的25.54%。图5 BMS产品2022年销售额图片来源：BMS 2022年报“阵地”还在，但有所松动。据BMS的2023年Q3财报显示，Eliquis前三个季度合计销售额为93.32亿美元，同比增长2.54%，而2022年同期销售额为91.01亿美元，同比增长达12.48%，增长有所放缓。图6 BMS产品2021年和2022年前三季销售情况图片来源：BMS 2021/2022年Q3财报其实BMS一直非常重视心血管“阵地”的防守，一方面，延长重磅药物专利保护期，2017年，美国专利商标局授予Eliquis一项关键组合物专利，保护期从2023年2月延至2026年11月；另一方面，寻找接力药物，2020年，BMS斥资131亿美元收购MyoKardia，增强心血管研发管线，获得了mavacamten。2022年4月，mavacamten获美国FDA批准上市，是FDA批准的首款用于HCM治疗的心肌肌凝蛋白变构调节剂，尽管BMS对mavacamten寄予厚望，预测其2029年销售将达40亿美元，但Eliquis成绩太好了，专利到期的市场缺口，不是Mavacamten就能弥补的。“魔法子弹”ADC近年来的大火，让BMS注意到其“胞弟”AOC，2021年，BMS子公司MyoKardia就与Avidity开展了合作，研究AOC在心脏组织中的潜在效用。上个月，诺和诺德在美国心脏协会（AHA）年度会议上公布了其有史以来开展的最大规模临床试验--司美格鲁肽心血管获益3期临床SELECT研究最新数据，患有心血管疾病与超重/肥胖症的17604名受试者入组，主要不良心血管事件风险降低20%，值得注意的是，受试者未患糖尿病。GLP-1的临床数据再次引爆了全球药企的追逐，面对未来Eliquis仿制药的围猎，以及GLP-1进军心血管领域的可能，BMS将重注押在了AOC上，从子公司合作升级到亲自“操刀”，且以购股方式与Avidity共进退。按合作协议计算，BMS将购入Avidity普通股超500万股，在众多持股者中，也算是“土豪级”了，这也为BMS以后在AOC上向心血管领域外拓展埋下了伏笔。图7 Avidity持股机构情况图片来源：东方财富网03不止AOC，BMS还有后手除了重押AOC巩固心血管“阵地”，BMS还留有后手，在2023年9月的研发日活动上，BMS透露了未来管线发展计划，在18个月内将注册资产数量翻一番，从6个增至12个，新注册资产关键管线更新包括：细胞疗法BMS-986353扩展到免疫疾病临床试验，包括严重难治性系统性红斑狼疮；潜在的first-in-class蛋白质降解剂golcadomide正在进入一线大B细胞淋巴瘤的3期临床试验；潜在的best-in-class BET抑制剂BMS-986158，用于骨髓纤维化，期待概念验证数据……另外，从BMS研发管线布局来看，在肿瘤学领域的布局最多，其次是血液学和免疫学领域，均比心血管领域丰富。图8 BMS研发布局管线图片来源：BMS官网就在研发日活动后不久，BMS就以最高58亿美元（含10亿美元潜在价值）收购Mirati，而Mirati的上市产品Krazati是全球第2款获批的KRAS药物，2022年12月获美国FDA加速批准，用于治疗KRAS G12C突变的局部晚期或转移性非小细胞肺癌（NSCLC）患者，而管线中，除了Krazati的适应症拓展外，MRTX1719、MRTX1133和MRTX0902，均用于肿瘤领域。图9 Mirati产品及管线图片来源：BMS官网在肿瘤学布局本来就最丰富的BMS，又收购Mirati，明显是加强和多样化肿瘤学投资组合，除了继续巩固心血管“阵地”，BMS欲将肿瘤领域推至“阵地”最前沿。04结语创新药赛道上从不缺乏爱冒险的勇士，在踏上赛道的那一刻起，无论将来成功与否，就注定了创新药“盲盒”打开时的刺激。BMS的押注，无论是巩固心血管领域地位，还是壮大肿瘤领域影响，都是大“赌局”，期待更精彩的表现。参考来源：1.Avidity官网2.BMS官网、财报3.凯莱英药闻官微《BMS：将心血管领域的未来，押注在AOC！》4.美迪西官微《小核酸抗体偶联药物(AOC)》声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | shara转载开白 | 马老师 18996384680（同微信）商务合作 | 张武龙 13368443108（同微信）阅读原文，是昨天最受欢迎的文章哦

抗体药物偶联物临床2期临床申请引进/卖出临床1期

2023-09-14

·Firstwordpharma

BMS targets doubling of registrational assets over next 18 months

At its R&D day on Thursday, Bristol Myers Squibb revealed that it intends to double its registrational pipeline from six to 12 new assets over the next 18 months. The company also indicated that cell therapy and targeted protein degradation platforms will take centre stage, offering the potential to expand treatment options across several therapeutic areas."We are seeing the impact of our focused efforts to strengthen our R&D engine and pipeline as we've executed against our priorities over the past four years," said Giovanni Caforio, who is set to retire from the role in November. "We are well-positioned to deliver more medicines to patients even faster in the future," he added.The pipeline update comes as Bristol Myers Squibb faces pressure from declining demand for Revlimid (lenalidomide) and Eliquis (apixaban), which face generic competition. The latter, which is partnered with Pfizer, also recently landed on the list of 10 drugs that will be subject to the first-ever price negotiations by the US Medicare programme.Three cell therapies that target immune disorders, cancerCandidates seen advancing include the CD19-directed NEX-T cell therapy BMS-986353, which Bristol Myers Squibb said it intends to move into clinical trials for immunologic diseases such as severe refractory systemic lupus erythematosus (SLE). BMS-986353 expresses the same CD19-specific CAR construct as Breyanzi (lisocabtagene maraleucel), but with a "differentiated safety profile" and enhanced manufacturing process, the company noted. Data from a Phase I trial in SLE is anticipated in 2024.Two other assets – the CAR-T BMS-986393, which is a potential first cell therapy targeting GPRC5D, and the BCMAxCD3 T-cell engager alnuctumab – are advancing into registrational testing for relapsed/refractory multiple myeloma, the latter in Phase III. The protein degrader golcadomide is also moving into Phase III next year for first-line large B-cell lymphoma.Meanwhile, a first asset from Bristol Myers Squibb's ligand-directed protein degradation platform, an androgen receptor degrader, is moving into pivotal studies in metastatic castration-resistant prostate cancer, while the BET inhibitor BMS-986158 for myelofibrosis is awaiting proof-of-concept data early next year.These would add to a batch of six candidates already in registrational trials, including the ROS1 inhibitor repotrectinib, which is currently under priority review at the FDA for non-small-cell lung cancer (NSCLC), with a decision date set for November 27. Protein degraders iberdomide and mezigdomide are both in registrational trials for second-line-plus multiple myeloma, with first data expected in 2026.The company is also developing the anti-IL-13 asset cendakimab for eosinophilic esophagitis, and milvexian in secondary stroke prevention, acute coronary syndrome and atrial fibrillation in collaboration with Johnson & Johnson. Meanwhile, Bristol Myers Squibb on Thursday also outlined Phase III trials for its LPA1 antagonist BMS-986278 in idiopathic pulmonary fibrosis and progressive pulmonary fibrosis that will evaluate both the 60mg and 120mg doses of the drug.

临床3期细胞疗法临床1期优先审批免疫疗法

100 项与 Ezobresib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15435

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
浆细胞骨髓瘤难治	临床2期	美国	Bristol Myers Squibb Co.	2022-10-18
浆细胞骨髓瘤难治	临床2期	加拿大	Bristol Myers Squibb Co.	2022-10-18
浆细胞骨髓瘤难治	临床2期	挪威	Bristol Myers Squibb Co.	2022-10-18
浆细胞骨髓瘤难治	临床2期	西班牙	Bristol Myers Squibb Co.	2022-10-18
浆细胞骨髓瘤难治	临床2期	英国	Bristol Myers Squibb Co.	2022-10-18
复发性多发性骨髓瘤	临床2期	美国	Bristol Myers Squibb Co.	2022-10-18
复发性多发性骨髓瘤	临床2期	加拿大	Bristol Myers Squibb Co.	2022-10-18
复发性多发性骨髓瘤	临床2期	挪威	Bristol Myers Squibb Co.	2022-10-18
复发性多发性骨髓瘤	临床2期	西班牙	Bristol Myers Squibb Co.	2022-10-18
复发性多发性骨髓瘤	临床2期	英国	Bristol Myers Squibb Co.	2022-10-18

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适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04817007 (CA011-023, ASH2023)	临床1/2期	原发性骨髓纤维化	40	BMS-986158+Ruxolitinib	鹹構鬱顧製網憲築觸積(範鬱範憲鹹淵繭構膚簾) = 醖遞鬱鹽鹹遞膚淵願遞夢鏇齋蓋願壓鑰蓋遞鏇 (積鹽網築襯繭壓齋齋窪 )	-	2023-12-10
				BMS-986158+Fedratinib	鹹構鬱顧製網憲築觸積(範鬱範憲鹹淵繭構膚簾) = 顧積遞簾鹹選築艱淵觸夢鏇齋蓋願壓鑰蓋遞鏇 (積鹽網築襯繭壓齋齋窪 )
NCT04817007 (CA011-023, ASH2022) 人工标引	临床1/2期	原发性骨髓纤维化	13	BMS 986158+Ruxolitinib	簾積醖膚積齋艱蓋衊構(壓膚獵製窪構獵構壓餘) = 衊願膚網獵選鹹艱齋鹽夢鏇顧觸壓觸鏇醖鹽壓 (廠廠選網膚鑰膚鹽鏇餘 ) 更多	积极	2022-11-15
				BMS 986158+Fedratinib	簾積醖膚積齋艱蓋衊構(壓膚獵製窪構獵構壓餘) = 鬱醖觸壓壓夢獵簾艱膚夢鏇顧觸壓觸鏇醖鹽壓 (廠廠選網膚鑰膚鹽鏇餘 ) 更多