替米沙坦对老年2型糖尿病肾病患者胰岛素抵抗和胰淀素分泌的影响

目的 探讨替米沙坦对老年2型糖尿病肾病患者胰岛素抵抗和胰淀素分泌的影响.方法 162例老年糖尿病肾病患者按尿蛋白排泄量(UAE)和血肌酐水平分为3组:早期肾病组、临床肾病组和肾功能减退组.每组再随机分为替米沙坦组(80 mg/d)和氯沙坦组(100 mg/d).测定治疗前后UAE、内生肌酐清除率、空腹血糖、空腹胰岛素和血胰淀素水平,计算胰岛素抵抗指数(HOMA-IR)和胰岛素敏感指数(ISI).结果 血胰淀素与UAE、空腹胰岛素、HOMA-IR呈正相关,与ISI呈负相关,与内生肌酐清除率和空腹血糖无关.替米沙坦能显著降低各期糖尿病肾病患者空腹胰岛素[(16.25±2.24)和(10.86±2.03)mIU/L,P＜0.01)]、HOMA-IR(4.16±0.42和3.07±0.28,P＜0.05)及血胰淀素水平[(27.76±4.34)和(18.21±3.03)pmol/L,P＜0.01],升高ISI.与氯沙坦各治疗组比较,差异均有统计学意义,且改善作用在早期肾病组更显著(P＜0.05).结论 替米沙坦能够改善不同分期老年2型糖尿病肾病患者胰岛素抵抗,降低血胰淀素水平,其作用优于对应剂量氯沙坦.     

糖尿病肾病患者血清白脂素水平与肾功能和糖代谢指标的相关性研究

目的探讨糖尿病肾病（DKD）患者血清白脂素（asprosin）水平与肾功能和糖代谢指标及临床意义。 方法选取2020年1月至2021年2月于惠州市中心人民医院就诊的2型糖尿病（T2DM）患者共84例,诊断为T2DM的患者共43例（T2DM组）,诊断为T2DM合并DKD的共41例（T2DM并DKD组）,健康体检的对照参与者40例作为对照组。收集所有参与者的体质量指数（BMI）、2型糖尿病病程、患者的收缩压（SBP）和舒张压（DBP）、肌酐（Cr）、尿素氮（BUN）、空腹血糖（FPG）、糖化血红蛋白（HbAlc）、空腹血清胰岛素（FINS）、胰岛素抵抗指数（HOMA-IR）,采用ELISA检测血清asprosin水平,并分析asprosin与相关指标的关系。 结果T2DM组的血清asprosin、Cr、FPG、HbAlc、FINS和HOMA-IR水平显著高于对照组,T2DM并DKD组的血清asprosin、Cr、FPG、HbAlc、FINS和HOMA-IR水平显著高于T2DM组和对照组（P<0.01）;血清asprosin水平与Cr、FPG、HbAlc、FINS的水平呈显著的正相关（P<0.01）,与年龄、BMI、SBP、DBP和BUN的水平没有显著的相关性（P>0.05）。 结论T2DM合并DKD患者的血清asprosin水平显著升高,且与肾功指标和糖代谢指标正相关。     

老年糖尿病患者胰岛β细胞功能及其与胰淀素和褪黑素的关系

目的观察新诊断老年糖尿病(DM)患者胰岛β细胞功能特点及其与胰淀素、褪黑素的关系。方法收集初诊DM患者60例,其中老年DM组27例,成年DM组33例,对照组30例。均行口服葡萄糖耐量试验(OGTT),计算胰岛β细胞功能指数(HOMA-β)。采用ELISA法检测患者空腹血清胰淀素、褪黑素水平。同时测定所有受试者的血脂、体重指数(BMI)和腰臀比(WHR),并对结果进行统计分析。结果 (1)老年DM组与成年DM组比较HOMA-β明显降低〔(58.20±24.89)vs(81.20±40.80),P0.01〕,而OGTT2h血糖、胰岛素值及胰岛素抵抗指数(HOMA-IR)明显升高(P均0.05)。(2)与对照组相比,老年DM组血清胰淀素水平显著增高〔(21.57±15.88)vs(17.82±12.15)ng/L,P0.01〕;而褪黑素水平明显降低〔(6.56±1.32)vs(7.65±1.39)pg/ml,P0.01〕。(3)老年糖尿病组HOMA-β与褪黑素呈正相关(r=0.403,P=0.016),与胰淀素(r=-0.461,P=0.003)、HOMA-IR(r=-0.238,P=0.009)呈负相关,与空腹血糖、胰岛素、甘油三酯(TG),WHR则无明显相关性。结论新诊断的老年DM患者存在明显的胰岛素分泌缺陷,胰淀素的增高和褪黑素的降低可能与老年糖尿病的发生有关。     

2型糖尿病患者外源性给予胰升血糖素对肥胖与血浆Ghrelin的影响

目的探讨肥胖及非肥胖2型糖尿病（T2DM）患者胰岛素抵抗（IR）与生长激素释放肽Gh—relin分泌的关系。方法肥胖T2DM患者26例（Ob＋T2DM组）及非肥胖T2DM患者32例（NOb＋T2DM组）,正常对照30名（NC组）行胰升血糖素－C-P释放试验,同步取血测定血浆Ghrelin和C-P。结果（1）Ob4-T2DM组空腹Ghrelin水平低于NC组和NOb＋T2DM组（P〈0．05或P〈0．01）;Ob＋T2DM组FC-P及胰岛素抵抗指数（HOMA2-IR）高于NC组和NOb＋T2DM组（P〈0．01或P〈0．05）。静脉推注胰升血糖素后,NC组Ghrdin水平显著下降（P〈0．01）,肥胖及非肥胖T2DM组Ghrelin水平无显著性改变。（2）Pearson相关分析显示空腹血浆Ghrelin水平分别与WC、BMI、体脂百分比、体脂重量呈负相关;多元回归分析显示腰围（WC）是Ghrelin水平的负性预测因子（回归方程Y=4．814—0．0265X）。（3）Ob＋T2DM组中,空腹血浆Ghrelin水平分别与WC、BMI、体脂百分比、体脂重量、HOMA2-IR呈负相关。结论外源性给予胰升血糖素对T2DM患者Ghrelin抑制效应减弱;肥胖T2DM患者血浆Ghrelin水平较非肥胖患者明显降低,且与WC、BMI、体脂百分比、体脂重量、HOMA2-IR负相关;中心性肥胖T2DM患者血浆Ghrelin水平下降与IR有关。     

2型糖尿病与胰淀素相关性的研究

选择正常人34例及2型糖尿病患者80例,检测空腹（FPG）及服馒头后两小时血糖（PPG）,血浆Amylin,胰岛素、C肽释放试验。测肝功、肾功、血脂、糖化血红蛋白（HbA1c）等。结果：2型糖尿病患者胰淀素的水平较正常人增高,餐后更明显,且与胰岛素的分泌有一定的相关性。结论：胰淀素水平的改变,能影响胰岛素的分泌,在糖尿病的发生、发展过程中起重要作用。     

初发2型糖尿病患者血清铁蛋白水平的变化及意义

目的探讨初发2型糖尿病（T2DM）患者降糖治疗前后血清铁蛋白（SF）水平的变化及临床意义。方法选择50例初发T2DM患者（T2DM组）经胰岛素和二甲双胍强化治疗2周,同期选择32例健康体检者作为对照组,检测对照组及T2DM组治疗前后血清SF、空腹血糖（FPG）、空腹胰岛素（FINS）、血脂等水平及BMI、胰岛素抵抗指数（HOMA-IR）、β细胞功能（HOMA-B）,并分析血清SF与各指标的相关性。结果 T2DM组HOMA-IR、收缩压（SBP）、TG、FPG及SF水平明显高于对照组（P均〈0.01）,HOMA-B、HDL-C明显低于正常对照组（P均〈0.01）,且SF水平与BMI、腰围、SBP、FPG、TG、HOMA-IR呈正相关（r分别为0.607、0.595、0.572、0.445、0.558、0.765,P均〈0.01）;与HDL-C呈负相关（r=-0.318,P〈0.05）。SF、BMI进入HOMA-IR多元回归方程,R2=0.674。结论初诊T2DM患者存在明显的胰岛素抵抗及铁超负荷,SF可能参与了T2DM的发生、发展。     

血清内脂素与肥胖和2型糖尿病的关系

目的 探讨血清内脂素与肥胖和2型糖尿病（T2DM）的相关性.方法 采用ELISA法检测100例T2DM患者（T2DM组）和80例健康者（对照组）的血清内脂素;测量其BMI及腰臀比（WHR）,检测空腹胰岛素（FINS）、空腹血糖（FPG）、餐后2 h血糖（2 h PG）、糖化血红蛋白（HbA1c）、血脂及胰岛素抵抗指数（HOMA-IR）;分析内脂素与BMI、WHR、血糖、血脂、HOMA-IR的关系.结果 T2DM组肥胖者（A1组）与非肥胖者（A2组）内脂素水平均高于对照组（P＜0.01）,且A1组高于A2组（P＜0.05）;内脂素水平与BMI、WHR、HbA1c、HOMA-IR、LDL-C呈负相关,与HDL-C呈负相关（P＜0.01或＜0.05）.结论 T2DM患者血清内脂素升高,并与肥胖相关;内脂素可能参与T2DM和肥胖的发病机制.     

不同糖耐量人群胰淀素水平相关性

目的探讨不同糖耐量人群胰淀素水平变化对血糖、胰岛β细胞功能等指标的影响。方法依血糖水平将患者分为2型糖尿病组、糖耐量异常组及正常对照组,测量血压、身高、体重,检测三组空腹血糖(FPG)、餐后2 h血糖(F 2 h PG)、空腹胰岛素(Fins)、餐后2 h胰岛素(F 2 h ins)、糖化血红蛋白(HbA1c)、胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、胰淀素(Amylin)等临床指标,计算体质量指数(BMI)、HOMA-IR、HOMA-β,比较三组间差异性及Amylin与各指标的相关性。结果三组间SBP、DBP、BMI、TC、TG、HDL-C、LDL-C、FPG、F 2 h PG、Fins、F 2 h ins、HOMA-IR、HOMA-β及Amylin水平均有显著性差异(P<0.05),糖尿病组Amylin与HbA1c、FPG、F 2 h PG及HOMA-IR水平呈显著负相关(P<0.05),与Fins、F 2 h ins呈显著正相关(P<0.05),与BMI、TC、TG、HDL-C、LDL-C及HOMA-β等指标无明显相关性(P>0.05),逐步多元回归分析提示Amylin水平是影响HOMA-IR的显著因素之一。结论胰淀素分泌异常会导致代谢紊乱,胰岛淀粉样沉积增多,损害β细胞功能,加重胰岛素抵抗。     

血浆内脂素水平与糖代谢异常相关性研究

目的测定2型糖尿病（T2DM）、空腹血糖受损（IFG）及糖耐量减低（IGT）患者血浆内脂素水平,探讨内脂素与体质量指数（BMI）、血糖、血脂及胰岛素抵抗的相关性。方法选取T2DM患者30例、IFG患者30例、IGT患者30例及正常对照组30例。采血测定内脂素、空腹血糖（FPG）、糖化血红蛋白（HbA1c）、血脂各项指标及空腹胰岛素（FINS）水平,计算BMI和腰臀比（WHR）,并以稳态模型计算胰岛素抵抗指数（HOMA—IR）及胰岛素分泌指数（HOMA-B）。结果T2DM组、IFG组及IGT组内脂素水平高于正常对照组,且IGT组高于IFG组。内脂素水平分别与BMI、WHR、FINS和HOMA-IR呈正相关,与HOMA—B呈负相关。逐步回归分析表明WHR、FPG、TG和BMI分别是影响血浆内脂素水平的独立相关因素。结论血浆内脂素水平与糖代谢状态有关,在T2DM的发生发展中具有一定的作用。     

单纯性肥胖与初诊2型糖尿病患者血清脂联素水平的研究

采用酶联免疫吸附法检测正常对照组,以及单纯肥胖组、初诊2型糖尿病（T2DM）非肥胖组及T2DM肥胖组患者的血清脂联素（ADIPO）水平。结果显示,T2DM患者ADIPO水平显著低于对照组和单纯肥胖组;女性显著高于男性;ADIPO水平与体质量指数、腰臀比、空腹血糖、甘油三酯及胰岛素抵抗指数呈负相关;与高密度脂蛋白胆固酵（HDL—C）呈正相关。提示初诊T2DM患者ADIPO明显降低,其水平存在显著性别差异,与肥胖、胰岛素抵抗、甘油三酯和HDL—C代谢相关。     

Circulating FGF-21 levels in normal subjects and in newly diagnose patients with Type 2 diabetes mellitus.

Fibroplast growth factor (FGF-21) is a recently discovered metabolic regulator. Its pathophysiologic role in humans remains unknown. In this study, we have investigated whether or not plasma FGF-21 level was different in patients with type 2 diabetes mellitus (T2DM) and non-diabetic controls. We also assessed associations between plasma FGF-21 body composition and several metabolic parameters. Fasting FGF-21 levels were significantly increased in patients with T2DM compared with controls (1.82+/-0.65 VS. 1.53+/-0.60 microg/L, P<0.05). In T2DM patients, fasting plasma FGF-21 correlate negatively with fasting blood glucose ( R= -0.31, P<0.05). Multiple regression analysis showed that FBG, plasma insulin and HOMA (IS) were independent influencing plasma FGF-21 levels. The present work suggests a potential role for FGF-21 in the pathogenesis of insulin resistance and T2DM.     

Insulin resistance contributes to obesity-related proteinuria

OBJECTIVE: Proteinuria is a recognized complication of obesity, but the pathogenesis remains unclear. We undertook the present study to clarify the factors contributing to proteinuria associated with obesity. METHODS: We studied 12 obese patients with proteinuria. Twenty-seven age-matched obese subjects without proteinuria served as controls. A glucose tolerance test and renal biopsy were performed in all patients. Fasting serum insulin and homeostasis model assessment-insulin resistance (HOMA-IR) were regarded as reflecting insulin resistance. To delineate the relation between insulin resistance and proteinuria, troglitazone, which acts an insulin sensitizer was given to 6 of 12 patients with a regular diet for 8 weeks. The 6 others were observed without receiving troglitazone. RESULTS: The 12 patients showed the presence of a cluster of insulin resistance factors: higher blood pressure, higher body mass index, higher fasting plasma glucose, higher fasting serum insulin, and higher HOMA-IR than controls. The renal biopsy specimens exhibited no histological abnormalities in 7, focal segmental glomerulosclerosis in 3 and benign nephrosclerosis in 2. Troglitazone attenuated HOMA-IR and ameliorated proteinuria, but did not affect body weight, creatinine clearance, or blood pressure. In contrast, the parameters in the patients not given troglitazone did not change. CONCLUSION: Insulin resistance is a factor contributing to obesity-related proteinuria. The role of insulin resistance as a factor reducing proteinuria remains to be clarified.     

2型糖尿病合并肥胖患者脂联素水平与胰岛素抵抗的相关性

目的 研究2型糖尿病合并肥胖患者脂联素水平和胰岛素抵抗之间的相关性,探讨脂联素在2型糖尿病合并肥胖患者发生胰岛素抵抗中的作用.方法 选择30例2型糖尿病合并肥胖患者、25例2型糖尿病患者及25例非糖尿病对照人员(其中13例为肥胖者),检测体质指数、腰/臀比值、空腹血糖、糖化血红蛋白、血清空腹胰岛素、血脂、脂联素水平,计算胰岛素抵抗指数和胰岛素敏感指数.分析血清脂联素与胰岛素抵抗的相关性.结果 (1)糖尿病肥胖组的检测体质指数、糖化血红蛋白、空腹血糖、胰岛素抵抗指数、血清空腹胰岛素、腰/臀比值均高于对照肥胖组,脂联素、胰岛素敏感指数低于对照肥胖组(P<0.05).(2)糖尿病非肥胖组甘油三酯、糖化血红蛋白、空腹血糖、胰岛素抵抗指数、血清空腹胰岛素均高于对照非肥胖组,胰岛素敏感指数、脂联素低于对照非肥胖组(P<0.05).(3)糖尿病肥胖组甘油三酯、胆固醇、体质指数、糖化血红蛋白、空腹血糖、胰岛素抵抗指数、血清空腹胰岛素、腰/臀比值均高于糖尿病非肥胖组,胰岛素敏感指数、脂联素低于糖尿病非肥胖组(P<0.05).结论 脂联素与2型糖尿病肥胖患者的胰岛素抵抗发生有关,脂联素降低易导致胰岛素抵抗,脂联素水平可作为2型糖尿病合并肥胖患者发生胰岛素抵抗的监测标准.     

国产吡格列酮治疗2型糖尿病患者的临床研究

目的观察国产吡格列酮对2型糖尿病(T2DM)病人血糖、血脂代谢和胰岛素抵抗(IR)的作用,并检测治疗前后血清脂联素水平的变化。方法用随机双盲法、与安慰剂平行对照,比较48例T2DM病人用吡格列酮30mg和安慰剂(1:1)干预治疗12w后的血糖、血脂、IR、血清脂联素水平改变。结果吡格列酮治疗12w后,空腹血糖和餐后2h(2hPG)血糖、糖化血红蛋白(HbA1c)与治疗前比较明显下降(P<0·05或P<0·01);空腹胰岛素(FINS)及HOMA模型IR指数(HOMA-IR)较治疗前也减低(P<0·05或P<0·01);血清脂联素水平、高密度脂蛋白(HDL-C)在12w治疗后显著升高,低密度脂蛋白(LDL-C)与治疗前比较明显降低(P<0·05或P<0·01),上述指标与安慰剂组比较差异均有显著意义(P<0·05或P<0·01)。但是总胆固醇(TC)、甘油三酯(TG)治疗前后无明显差异。结论国产吡格列酮可改善T2DM病人血糖及血脂代谢,降低IR并升高血清脂联素水平,有助于防治T2DM血管并发症。     

非酒精性脂肪性肝病胰岛素抵抗程度与全血细胞计数的相关性

目的探讨伴或不伴2型糖尿病(T2DM)的非酒精性脂肪性肝病(NAFLD)胰岛素抵抗(IR)程度与全血细胞计数各参数的相关性。方法选取糖耐量正常并除外糖尿病史的单纯NAFLD患者102例,T2DM合并NAFLD患者104例,正常对照104例为研究对象,测定空腹血糖(FPG)、空腹胰岛素(FINS)和全血细胞计数,分析胰岛素抵抗指数(HOMA-IR)与全血细胞计数各参数的相关性。结果 T2DM合并NAFLD患者IR及全血细胞计数异常程度较单纯NAFLD患者更重;相关性研究表明男性HOMA-IR与WBC、NEU、LYM、RBC、HGB、HCT呈正相关,女性HOMA-IR与WBC、NEU、LYM、MID、RBC、HGB、HCT呈正相关。结论 NAFLD时白细胞参数和红细胞参数的变化与IR密切相关,T2DM的存在加重了IR对上述血细胞参数的影响。全血细胞计数可以作为反映NAFLD患者IR程度的一种简单实用的检验指标。     

不同糖化血红蛋白水平的2型糖尿病患者血浆皮质醇水平及临床意义

目的探讨不同糖化血红蛋白(HbA1c)水平的2型糖尿病(T2DM)患者血清皮质醇水平与血糖、胰岛素抵抗的相关性。方法选取2019年3月—2020年5月期间在该院检测过皮质醇的T2DM患者106例,分为HbA1c≤7%。7%组和HbA1c>7%组。对比分析两组患者的血清皮质醇(8:00)水平的差异以及其与空腹血糖(FBG)、HbA1c、HOMA指数(HOMA-IR)之间的相关性。结果HbA1c>7%组的血清皮质醇(8:00)、FBG、HbAlc及HOMA-IR水平显著高于HbA1c≤7%组,差异有统计学意义(P<0.05);全部T2DM患者血清皮质醇(8:00)水平与FBG、HbA1c呈正相关(P<0.05)。结论T2DM患者存在血清皮质醇(8:00)水平增高,且皮质醇分泌过高的程度与患者血糖水平的高低密切相关,可将血浆皮质醇作为血糖控制情况的评价指标之一。     

Serum gamma-glutamyl transpeptidase is a determinant of insulin resistance independently of adiposity in Pima Indian children

CONTEXT: Elevated activities of serum enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT), have been associated with obesity and insulin resistance (IR). ALT is an independent predictor of type 2 diabetes mellitus (T2DM) in adult Pima Indians, and GGT predicts T2DM in other adult populations. OBJECTIVE: Our aim was to establish whether independent relationships exist between either adiposity or IR and hepatic enzymes in a group of Pima Indian children. SUBJECTS AND METHODS: In a cross-sectional study, 44 children (22 males and 22 females; 7-11 yr old) were measured for weight (WT), height, percent body fat, and serum activities of ALT, AST, and GGT. Body mass index (kilograms per meter squared) was calculated. IR was calculated from fasting plasma concentrations of glucose and insulin using the homeostasis model assessment (HOMA-IR). RESULTS: Hepatic enzymes were positively associated with obesity measures, fasting insulin, and HOMA-IR. GGT was additionally associated with serum lipids and white blood cell count. GGT, but not AST or ALT, was a significant determinant of HOMA-IR independently of age, sex, and WT, body mass index, or percent body fat. The model that accounted for the largest portion of the variance in HOMA-IR included WT (beta = 0.004; P = 0.008) and GGT (beta = 0.20; P = 0.004; total R(2) = 0.62; P < 0.0001). CONCLUSION: Significant relationships between adiposity and hepatic enzyme activities exist during childhood in Pima Indians. Whether serum GGT activity predicts the development of T2DM in these children remains to be determined in follow-up studies.     

血浆睾酮水平对中青年男性2型糖尿病患者罹患代谢综合征的影响

目的 探讨血浆睾酮水平对中青年男性2型糖尿病（T2DM）患者罹患代谢综合征（MS）的影响.方法 共纳入220例年龄在18 ～50岁的男性2型糖尿病患者,按照血浆睾酮浓度四分位分组,搜集一般资料、吸烟史及人体测量学指标,检测患者空腹血糖、空腹胰岛素、血脂、糖化血红蛋白（HbAlc）水平.结果 随血浆睾酮浓度升高,MS发病率下降（P＜0.05）,吸烟者比例、年龄、糖尿病病程、腰围、体重指数（BMI）、收缩压（SBP）、舒张压（DBP）、HbAlc、HOMA-IR、三酰甘油（TG）、总胆固醇（TC）及低密度脂蛋白胆固醇（LDL-C）等均降低（P＜0.01或P＜0.05）.相关性分析显示,血浆睾酮浓度与年龄、吸烟、糖尿病病程、腰围、BMI、SBP、DBP、HbAlc、HOMA-IR、TG、TC及LDL-C等均呈负相关（P＜0.01或P＜0.05）.Logistic回归分析显示,血浆睾酮为中青年男性2型糖尿病患者罹患MS的保护性因素,其OR值为0.479（95％CI：0.249 ～0.936,P＜0.01）,在校正年龄、吸烟、糖尿病病程、HOMA-IR及HbAlc后其OR值上升为0.759（95％CI：0.598 ～ 0.963,P＜0.05）.结论 中青年男性2型糖尿病患者血浆睾酮水平与代谢综合征呈负相关,低血浆睾酮可能是其罹患谢综合征的独立危险因素.     

Comparison of metabolic profile and adiponectin level with pioglitazone versus voglibose in patients with type-2 diabetes mellitus associated with metabolic syndrome

Type 2 diabetes mellitus (T2DM) associated with metabolic syndrome (MetS) represents a high risk of cardiovascular disease. We compared the effect of early intervention with pioglitazone versus voglibose on physical and metabolic profiles and serum adiponectin level in patients with T2DM associated with MetS. Sixty patients who were diagnosed for the first time as T2DM associated with MetS were analyzed for insulin sensitivity, lipid profile, serum adiponectin and systemic inflammation. Those patients were randomly assigned to oral pioglitazone group (n = 30) or voglibose group (n = 30) in addition to conventional diet and exercise training. Body mass index and waist circumference did not change in the pioglitazone group, whereas these physical parameters significantly decreased in the voglibose group during a 6-month follow-up period. However, glycosylated hemoglobin, fasting plasma glucose, and HOMA-IR more significantly decreased in the pioglitazone group. The level of serum adiponectin especially high-molecular weight adiponectin markedly increased in the pioglitazone group. Moreover, high sensitive CRP significantly decreased only in the pioglitazone group. These results suggest that voglibose is superior in improving obesity, while pioglitazone is superior in ameliorating insulin sensitivity and increasing serum adiponectin in patients with an early stage of T2DM associated with MetS.