两种三联疗法和两种四联疗法根除Hp感染的临床疗效分析

目的 比较两种三联疗法和两种四联疗法根除Hp感染的疗效。方法将Hp阳性PU280例随机分为三联组、四联组。三联组中A1组70例用奥美拉唑+阿莫西林+克拉霉素,A2组70例用奥美拉唑+阿莫西林+甲硝唑;四联组中B1组70例用雷贝拉唑+丽珠得乐+阿莫西林+呋喃唑酮,B2组70例用兰索拉唑+丽珠得乐+阿莫西林+呋喃唑酮。各组疗程均为1周,疗程结束4周后复查胃镜检测Hp。结果各组Hp根除率分别为A176.9%、A279.7%、B198.5%、B296.7%,三联组平均根除率为78.3%,四联组平均根除率为97.6%。四联组Hp根除率高于三联组(P<0.05),两种疗法组内比较均无统计学差异(P>0.05)。结论与三联疗法比较,四联疗法用于Hp感染的初治,具有根除率高、成本低、副反应小等特点,应作为首选。     

左氧氟沙星三联疗法复治幽门螺杆菌感染34例临床观察

目的观察左氧氟沙星、兰索拉唑、阿莫西林三联疗法对幽门螺杆菌(Hp)治疗失败后的患者复治的疗效。方法经抗Hp一线治疗后C14呼气试验仍阳性,62例慢性胃炎病例,随机分为治疗组和对照组,治疗组34例,左氧氟沙星、兰索拉唑、阿莫西林三联疗法。对照组28例,奥美拉唑、铋剂、阿莫西林、甲硝唑四联疗法,比较两组的治疗结果。结果治疗组对再次治疗病例Hp根除率为85.29%,对照组为75%,两组Hp比较无统计学意义(P>0.05)。结论左氧氟沙星、兰索拉唑、阿莫西林三联疗法对Hp治疗失败后的Hp根除率与以铋剂为基础加质子泵抑制剂(PPl)的四联疗法对Hp的根除率接近,但用药简单,患者易于接受。     

四联疗法一线治疗幽门螺杆菌感染疗效研究

目的 探讨含铋剂四联7 d疗法一线治疗幽门螺杆菌感染的临床疗效.方法 120例既往未接受过根除治疗的Hp 感染患者,随机分配至三联组和四联组,三联组给予兰索拉唑30 mg +阿莫西林1.0 g + 克拉霉素250 mg,(2次/d) 治疗7d,四联组给予兰索拉唑30 mg +阿莫西林1.0 g + 克拉霉素250 mg + 胶体果胶铋150 mg,(2次/d),治疗7 d.疗程结束4周后行13c-尿素呼气试验检查,结果阴性者判断为Hp根除,同时观察治疗过程中症状缓解率和不良反应.结果 四联组Hp的根除率均明显高于三联组,差异有统计学意义(P< 0.05).两组症状缓解率和不良反应发生率相似,差异无统计学意义(P>0.05).结论 含铋剂四联7 d疗法根除幽门螺杆菌初治疗效高于标准三联7 d疗法.     

标准三联疗法四联疗法及序贯疗法根除幽门螺杆菌的疗效观察

目的比较标准三联疗法、四联疗法及序贯疗法根除幽门螺杆菌(Hp)的疗效及安全性。方法300例非溃疡性消化不良者随机入选三联、四联及序贯疗法组,三联疗法组予兰索拉唑+阿莫西林+克拉霉素治疗10d。四联疗法组予兰索拉唑+胶体次枸橼酸铋+阿莫西林+克拉霉素治疗10d。序贯疗法组前5d予兰索拉唑+阿莫西林治疗,后5d予兰索拉唑+克拉霉素+甲硝唑治疗。治疗结束至少停药4周后复查14 C尿素呼气试验,结果阴性表示根除成功。同时评估疗效及安全性。对Hp根除率进行意向性分析和符合方案分析比较。结果意向性分析显示三联疗法组、四联疗法组及序贯疗法组的Hp根除率分别是66%(66/100)、82%(82/100)及84%(84/100)。符合方案分析显示三联疗法组、四联疗法组及序贯疗法组的Hp根除率分别是72%(66/92)、91%(82/90)及89%(84/94)。意向性分析及符合方案分析均表明三联疗法组Hp根除率明显低于四联疗法组或序贯疗法组,差异有统计学意义(P均<0.05),而四联疗法组与序贯疗法组间差异无统计学意义(P>0.05)。结论四联疗法或序贯疗法可作为临床根治Hp的一线治疗方案。     

四联疗法和三联疗法根除幽门螺杆菌感染的对比分析

目的对比四联（果胶铋、奥美拉唑、阿莫西林、甲硝唑）一周疗法和三联（果胶铋、阿莫西林、甲硝唑）两周疗法根除幽门螺杆菌（Hp）的效果及安全性。方法将37例经胃镜或尿素酶试验或14C．尿素呼气试验证实的十二指肠溃疡、胃溃疡及慢性胃炎HP阳性患者随机分入四联疗法组和三联疗法组治疗。四联疗法组（25例）用果胶铋100mg,每日4次;奥美拉唑20mg,2次／d;阿莫西林500mg,4次／d;甲硝唑400mg,2次／d;疗程一周。三联组（12例）果胶铋、阿莫西林、甲硝唑用量与用法与四联组相同,不包括奥美拉唑,疗程2周。结果四联疗法组腹痛缓解率为88％,HP根除率为88％,不良反应发生率为30％,三联疗法组分别为75％、83％和25％,两组比较无显著性差异。结论四联疗法和三联疗法都具有较好疗效及Hp清除率。而四联疗法因疗程缩短,更经济合理,是较为理想的方案。     

含铋剂四联疗法初次根除幽门螺杆菌感染疗效观察

目的:观察含铋剂四联疗法初次根除幽门螺杆菌(Hp)感染十二指肠溃疡(DU)的临床疗效和安全性。方法:Hp阳性DU患者160例分为治疗组和对照组各80例。治疗组给予枸橼酸铋钾胶囊600 mg+泮托拉唑片40mg+阿莫西林胶囊1 000mg+呋喃唑酮片100 mg,po bid。对照组给予泮托拉唑胶囊40 mg+阿莫西林片1 000 mg+甲硝唑片400 mg,po bid。两组均治疗14 d。治疗结束4周判断Hp根除情况。结果:治疗组和对照组Hp根除率分别为90.00%和76.25%,差异有统计学意义(P<0.05)。结论:含铋剂四联疗法可作为感染Hp的DU活动期初次治疗的一线方案。     

H2RA与PPI三联疗法对根除Hp效果的比较

目的：研究H2－受体拮抗剂（H2RA）三联疗法与质子泵抑制剂（PPI）三联疗法及其1周与2周疗法对根除幽门螺杆菌（H.pylori,Hp)的效果。方法：128例Hp阳性的胃炎和十二指肠溃疡患者随机分成H2RA三联组和PPI三联组。H2RA三联组（法莫替丁20mg,bid 阿莫西林1.0g,bid 甲硝唑0.4g,bid，疗程1或2周），PPI三联组（奥美拉唑20mg,bid 阿莫西林1.0g,bid 甲硝唑0.4g,bid，疗程1或2周）。疗程结束后4周复查Hp。结果：H2RA三联与PPI三联疗法Hp根除率1周分别为56．0％和76．9％；2周为81．6％和82．1％。结论：H2RA三联疗法2周的Hp根除率明显高于1周Hp根除率（P＜0．05），但PPI三联疗法1周与2周无统计学差异（P＞0．05）。H2RA三联疗法与PPI三联疗法的Hp根除率无统计学差异。     

兰索拉唑三联疗法根除幽门螺杆菌的成本-效果分析

目的：对3种兰索拉唑三联疗法治疗幽门螺杆菌感染的方案进行经济学评价。方法：将85例经胃镜确诊为胃或十二指肠溃疡伴Hp阳性患者随机分为3组。LCA组,口服阿莫西林胶囊（A）1.0g,bid;LCF组,口服呋喃唑酮片（F）0.2g,bid;LCZ组,口服左氧氟沙星胶囊（Z）0.2g,bid,并且3组同时口服兰索拉唑（L）30mg,bid,克拉霉素颗粒剂（C）500mg,bid,疗程均为7日。三联治疗结束后再分别予以兰索拉唑30mg,qd,整个疗程为3周,采用药物经济学的成本-效果法进行分析。结果：3组Hp根除率和溃疡愈合率差异无显著性,但治疗成本不同。结论：LCF三联疗法成本最低,并且效果最好。     

三联疗法治疗Hp阳性的小儿消化性溃疡疗效观察

目的:比较克拉霉素加胶体次枸橼酸铋加甲硝唑短程联用与传统三联疗法治疗对Hp阳性的小儿消化性溃疡的疗效。方法:将68例消化性溃疡患儿随机分为治疗组35例,用克拉霉素(CLA)加胶体次枸橼酸铋(CBS)加甲硝唑(Met)治疗,疗程均为1周;对照组33例用阿莫西林(AMO)加胶体次枸橼酸铋(CBS)加甲硝唑(Met)三联疗法,疗程为2周。治疗中观察腹痛消失天数,停药4周后复查对照观察腹痛缓解率、溃疡愈合率及幽门螺杆菌(Hp)根除率。结果:在腹痛缓解率、溃疡愈合率及幽门螺杆菌(Hp)根除率方面,治疗组分别为96.14%、96.14%和94.29%,而对照组分别为90.91%、87.88%和87.88%,校正卡方检验,两组比较差异无显著性(P>0.05);治疗中腹痛消失时间,治疗组(1.52±0.45)天,对照组(3.56±1.21)天,两组比较差异有显著性(P<0.05)。结论:用克拉霉素三联短疗程疗法治疗小儿消化性溃疡能有效的根除Hp,促进溃疡愈合,与阿莫西林三联疗法相似,但腹痛消失时间优于阿莫西林三联疗法。     

以加替沙星为基础的三联疗法根除幽门螺杆菌感染的疗效和费用分析

目的:观察以加替沙星为基础的多种三联疗法根除幽门螺杆菌(Hp)的疗效、不良反应和药品费用,以探讨临床较佳的根除Hp的方案。方法:采用分组对照的研究方法,并应用药物经济学方法分析各方案的费用效果(C/E)比。初次根除Hp共175例分为:A组为加替沙星200mg,bid,甲硝唑0.4g,bid,兰索拉唑30mg,bid;B组为加替沙星400mg,qd,甲硝唑0.4g,bid,兰索拉唑30mg,bid;C组为加替沙星400mg,qd,甲硝唑0.4g,bid,雷贝拉唑10mg,qd;D组为克拉霉素0.5g,bid,甲硝唑0.4g,bid,兰索拉唑30mg,bid。E组为再次根除Hp共17例,方案同A组。疗程为7d。结果:A,B,C,D组的Hp根除率分别为90%,91%,92%,84%,A,B,C和D组间无显著差异(P>0.05)。E组根除率为82%。不良反应总发生率为25%,A+E组与C或D组组间有非常显著差异(P<0.01),B组与C组间无显著差异(P>0.05)。A,B,C,D,E组的C/E分别为3.44,3.40,2.76,4.41,3.77,应用加替沙星组总的C/E为3.34。结论:加替沙星能有效地根除Hp,不良反应少。根除Hp及费用以A,B两组方案较优,C组方案最优。     

枸橼酸铋雷尼替丁为基础治疗萎缩性胃炎患者Hp的疗效观察

目的应用枸橼酸铋雷尼替丁(RBC)与克拉霉素+阿莫西林三联7d疗法根除幽门螺杆菌(Hp),评估以RBC为基础的三联方案的疗效。方法萎缩性胃炎120例随机分为R组和O组,每组60例,R组为RBC 350 mg+克拉霉素0.5 g+阿莫西林1 g,2次/d,口服;O组为奥美拉唑(OME)20 mg+克拉霉素0.5 g+阿莫西林1 g,2次/d,口服,疗程均为7 d。停药28 d后检查14C尿素呼气试验,如阴性表示根除成功,观察两组Hp阴转率。结果两组Hp阴转率分别为83.02%和71.15%,差异无统计学意义(P>0.05)。结论 R组根除萎缩性胃炎患者Hp感染,其Hp阴转率与O组相当。     

含左氧氟沙星的三种方法根除幽门螺杆菌疗效比较

目的比较含左氧氟沙星的三联疗法、铋剂四联疗法及序贯疗法根治幽门螺杆菌（Hp）的疗效。方法115例Hp阳性患者按时间先后顺序随机分为3组：三联组38例,给予口服兰索拉唑胶囊30mg、阿莫西林克拉维酸钾片685．5mg、左氧氟沙星胶囊200mg,2次／d,治疗7d;四联组38例,予以口服兰索拉唑胶囊30mg、阿莫西林克拉维酸钾片685．5mg、左氧氟沙星胶囊200mg、胶体果胶铋胶囊200mg,2次／d,7d;序贯组39例,前5d口服兰索拉唑胶囊30mg、阿莫西林克拉维酸钾片685．5mg,后5d口服兰索拉唑胶囊30mg、克拉霉素片500mg、左氧氟沙星胶囊200mg,均2次／d。疗程结束后4周复查”C呼气试验检查,评估治疗结果及不良反应。结果三联组完成35例,失访2例,未能按要求服药1例;铋剂四联组完成36例,失访2例;序贯组完成37例,未能按要求服药2例。三联组成功根除29例,按符合方案（PP）分析根除率为82．9％（29／35）,意向性治疗（ITT）分析根除率为76．3％（29／38）;铋剂四联组成功根除32例,PP根除率为88．9％（32／36）,ITT根除率为84．2％（32／38）;序贯组成功根除34例,PP根除率为91．9％（34／37）,ITT根除率为87．2％（34／39）。3组间Hp根除率差异无统计学意义（P〉0．05）。结论含左氧氟沙星的铋剂四联与序贯治疗均有较高的Hp根除率,但从安全性与疗效方面考虑,含左氧氟沙星的铋剂四联疗法可作为Hp初治的首选方案。     

四联疗法作为二线方案根除幽门螺杆菌感染的疗效

目的 :观察 2种四联疗法作为二线方案根除幽门螺杆菌 (Hp)感染的疗效。方法 :10 8例经以质子泵抑制药为基础的三联疗法根除Hp失败或根除后复发的病人 ,分为A组 5 4例和B组 5 4例。 2组均予奥美拉唑 2 0mg、胶体次枸椽酸铋 2 4 0mg及甲硝唑 4 0 0mg ,po ,bid ,A组加四环素 5 0 0mg ,po ,qid ;B组加阿莫西林 10 0 0mg ,po ,bid ;疗程均为 7d。疗程结束 1mo后复查Hp。结果 :A ,B 2组Hp根除率按方案分析分别为 82 % (42 / 5 1)和 81%(42 / 5 2 ) ,按意图治疗分析均为 78% (42 / 5 4)。 2组不良反应发生率分别为 2 3% (15 / 5 3)和 11% (6 /5 3)。 2组间疗效比较差异无显著意义 (P >0 .0 5 )。结论 :2种四联疗法作为二线方案根除幽门螺杆菌均有良好的疗效 ,且疗效相近 ,无严重不良反应     

两种三联疗法治疗幽门螺杆菌相关的十二指肠溃疡

目的;观察两种三联疗法治疗幽门螺杆菌相关的十二指肠溃疡。方法：６６例甲硝唑敏感的患者随机分为两组,铋剂组：ｐｏ德诺２４０ｍｇ ｂｉｄ,克拉霉素５００ｍｇ ｔｉｄ,甲硝唑４００ｇ ｂｉｄ,奥美拉唑组（３２例）：ｐｏ奥美拉唑唑２０ｍｇ ｑｄ,羟氨苄青霉素５００ｍｇ ｔｉｄ,甲硝唑４００ｍｇ ｂｉｄ。     

Ranitidine bismuth citrate‐based triple therapies after failure of the standard ‘Maastricht triple therapy’: a promising alternative to the quadruple therapy?

BACKGROUND: Triple therapy with proton pump inhibitor, clarythromycin, and amoxicillin has been proposed in Maastricht as the first-line treatment of H. pylori infection. AIM: To determine whether ranitidine bismuth citrate (RBC) based regimens may be used as second-line treatments after 'Maastricht therapy' failure. METHODS: A total of 285 patients with H. pylori infection were given a 7-day treatment with pantoprazole 40 mg b.d., clarythromycin 500 mg b.d., and amoxicillin 1 g b.d. Patients who were still infected were randomly given one of the following 14-day treatments: RBC 400 mg b.d. plus amoxicillin 1 g b.d. and tinidazole 500 mg b.d. (RAT group), RBC 400 mg b.d. plus amoxicillin 1 g b.d. and clarythromycin 500 mg b.d. (RAC group), and RBC 400 mg b.d. plus clarythromycin 500 mg b.d. and tinidazole 500 mg b.d. (RCT group). RESULTS: The 'Maastricht therapy' achieved an eradication rate of 59% (95% CI: 54-65) on intention-to-treat analysis. The RAT, RAC, and RCT regimens achieved eradication rates of 81% (95% CI: 67-94), 43% (95% CI: 26-60), and 62% (95% CI: 44-80), respectively, on intention-to-treat analysis. Patient compliance was optimal in RAT and RAC groups. CONCLUSION: RBC plus tinidazole and either amoxicillin or clarythromycin can be used as second-line therapies after failure of the Maastricht triple therapy.     

One-week ranitidine bismuth citrate,amoxicillin and metronidazole triple therapy for the treatment of Helicobacter pylori infection in Chinese

BACKGROUND: We have previously shown that ranitidine bismuth citrate-based, clarithromycin-containing triple therapy achieves a higher eradication rate than proton pump inhibitor-based regimens in areas with a high prevalence of metronidazole resistance. AIM: To evaluate whether this higher efficacy of ranitidine bismuth citrate over proton pump inhibitor can be extended to non-clarithromycin-containing regimens. METHODS: Helicobacter pylori-positive dyspeptic patients were randomized to receive either ranitidine bismuth citrate, 400 mg, amoxicillin, 1000 mg, and metronidazole, 400 mg, or omeprazole, 20 mg, amoxicillin, 1000 mg, and metronidazole, 400 mg, each given twice daily for 1 week. H. pylori eradication was confirmed by 13C-urea breath test 5 weeks later. The side-effects of the treatments were documented. RESULTS: Two hundred and twenty-nine patients were eligible for analysis. By intention-to-treat and per protocol analysis, the eradication rates were 77% and 79%, respectively, in the ranitidine bismuth citrate-amoxicillin-metronidazole group and 77% and 82%, respectively, in the omeprazole-amoxicillin-metronidazole group (P = 0.58 and P = 0.65). However, patients in the omeprazole-amoxicillin-metronidazole group reported a significantly higher incidence of minor side-effects when compared to those in the ranitidine bismuth citrate-amoxicillin-metronidazole group (P = 0.001). CONCLUSIONS: Ranitidine bismuth citrate-amoxicillin-metronidazole was equally as effective as omeprazole-amoxicillin-metronidazole triple therapy, and may be considered as an alternative non-clarithromycin-based regimen in the Chinese population.     

兰索拉唑、阿奇霉素和甲硝唑根除幽门螺杆菌的疗效-费用观察

目的 :观察兰索拉唑、阿奇霉素和甲硝唑短程低剂量三联疗法根除幽门螺杆菌 (Hp)的临床疗效和治疗费用。方法 :将 4 7例病人随机分为 2组 :治疗组 2 4例给兰索拉唑 30mg ,po ,qd× 1wk ,阿奇霉素 5 0 0mg ,po ,qd× 3d ,甲硝唑 4 0 0mg ,po ,bid× 3d。对照组 2 3例给奥美拉唑 2 0mg ,po ,bid× 1wk ,克拉霉素 5 0 0mg ,po ,bid× 1wk ,甲硝唑4 0 0mg ,po ,bid× 1wk。停药 1mo后采用14 C呼气试验复查Hp。结果 :治疗组和对照组Hp根除率分别为 92 %和 91% (P >0 .0 5 ) ;治疗费用为185 .84元和 6 2 3.96元 ;药物不良反应发生率 4 %和9% (P >0 .0 5 )。结论 :兰索拉唑、阿奇霉素和甲硝唑短程低剂量三联疗法根除Hp有较好效果 ,且治疗药品费用低 ,病人依从性好     

Randomized study of different 'second-line' therapies for Helicobacter pylori infection after failure of the standard 'Maastricht triple therapy'

BACKGROUND: Triple therapy with proton pump inhibitor, clarithromycin and amoxicillin and, in the event of eradication failure, quadruple therapy with proton pump inhibitor, bismuth, tetracycline and metronidazole have been proposed in Maastricht as the optimal sequential treatment of Helicobacter pylori infection. AIM: To compare two second-line regimens with quadruple therapy. METHODS: One hundred and eighty patients with a previous failed course of standard therapy were randomly given one of the following 7-day treatments: ranitidine bismuth citrate 400 mg b.d. plus amoxicillin 1 g b.d. and tinidazole 500 mg b.d. (RBCAT), pantoprazole 40 mg b.d. plus amoxicillin 1 g b.d. and levofloxacin 500 mg/day (PAL) and pantoprazole 40 mg b.d., bismuth citrate 240 mg b.d., tetracycline 500 mg q.d.s. and metronidazole 500 mg b.d. (PBTM). The eradication rate was assessed by 13C-urea breath test. Side-effects and compliance were evaluated by a standardized questionnaire and by counting returned medication. RESULTS: The RBCAT, PAL and PBTM groups achieved mean intention-to-treat eradication rates of 85%, 63% and 83%, respectively (P<0.05 for PAL vs. either RBCAT or PBTM). Compliance was optimal in all patients, although side-effects were more commonly observed in the PBTM group than in the other two patient groups (P<0.0001). CONCLUSIONS: Both RBCAT and PBTM can be used as second-line therapies. Conversely, PAL did not achieve satisfactory eradication rates.     

One-week ranitidine bismuth citrate-based triple therapy for the eradication of Helicobacter pylori in Hong Kong with high prevalence of metronidazole resistance

AIM: To compare 1-week ranitidine bismuth citrate-based (RBC) triple therapy vs. omeprazole-based (O) triple therapy for the eradication of Helicobacter pylori infection in Hong Kong with high prevalence of metronidazole resistance. METHODS: Patients with non-ulcer dyspepsia and H. pylori infection were randomized to receive either: (i) RBCCM: ranitidine bismuth citrate (pylorid) 400 mg, clarithromycin 250 mg and metronidazole 400 mg; or (ii) OCM: omeprazole 20 mg, clarithromycin 250 mg and metronidazole 400 mg, each given twice daily for 1 week. Endoscopy (CLO test, histology and culture) and 13C-urea breath test were performed before randomization and 6 weeks after drug treatment. RESULTS: A total of 180 patients were randomized. H. pylori eradication rates (intention-to-treat, n=180/per protocol, n=166) were 83%/92% for RBCCM and 66%/70% for OCM (P=0.01, intention-to-treat and P=0.001, per protocol, respectively). RBCCM treatment was unaffected by metronidazole susceptibility and achieved a significantly higher eradication rate in metronidazole-resistant cases (89%) than the OCM group (45%, P=0.0064). CONCLUSION: One-week ranitidine bismuth citrate-based triple therapy is significantly better than omeprazole-based triple therapy for the eradication of H. pylori infection, especially in metronidazole-resistant cases. It is an effective regimen for the eradication of H. pylori infection in regions with a high prevalence of metronidazole resistance.     

Lansoprazole, levofloxacin and amoxicillin triple therapy vs. quadruple therapy as second-line treatment of resistant Helicobacter pylori infection

AIM: To test the efficacy of levofloxacin-based second-line therapy for resistant Helicobacter pylori infection. METHODS: One hundred and six patients who failed H. pylori eradication were randomized to receive (i) lansoprazole 30 mg, amoxicillin 1 g, levofloxacin 500 mg, all given twice daily for 7 days (LAL); or (ii) lansoprazole 30 mg twice daily, metronidazole 400 mg thrice daily, bismuth subcitrate 120 mg and tetracycline 500 mg four times daily for 7 days (quadruple). Post-treatment H. pylori status was determined by (13)C-urea breath test. RESULTS: Intention-to-treat and per-protocol H. pylori eradication rates were 57/60% for the LAL group and 71/76% for the quadruple group respectively. Metronidazole, clarithromycin, amoxicillin and levofloxacin resistance were found in 76%, 71%, 0% and 18% of patients, respectively. Levofloxacin resistance led to treatment failure in the LAL group. For patients with dual resistance to metronidazole and clarithromycin, the eradication rates were 79% in the LAL group (levofloxacin-sensitive) and 65% in the quadruple group (P=0.34). CONCLUSION: Lansoprazole, amoxicillin plus levofloxacin second-line therapy is comparable with quadruple therapy in efficacy. Subjects, especially those with dual resistance to metronidazole and clarithromycin, may consider levofloxacin-based therapy for levofloxacin-sensitive strains.