Case-control study of stroke and the quality of hypertension control in north west England.

OBJECTIVE: To examine the risk of stroke in relation to quality of hypertension control in routine general practice across an entire health district. DESIGN: Population based matched case-control study. SETTING: East Lancashire Health District with a participating population of 388,821 aged < or = 80. SUBJECTS: Cases were patients under 80 with their first stroke identified from a population based stroke register between 1 July 1994 and 30 June 1995. For each case two controls matched with the case for age and sex were selected from the same practice register. Hypertension was defined as systolic blood pressure > or = 160 mm Hg or diastolic blood pressure > or = 95 mm Hg, or both, on at least two occasions within any three month period or any history of treatment with antihypertensive drugs. MAIN OUTCOME MEASURES: Prevalence of hypertension and quality of control of hypertension assessed by using the mean blood pressure recorded before stroke) and odds ratios of stroke (derived from conditional logistic regression). RESULTS: Records of 267 cases and 534 controls were examined; 61% and 42% of these subjects respectively were hypertensive. Compared with non-hypertensive subjects hypertensive patients receiving treatment whose average pre-event systolic blood pressure was controlled to < 140 mm Hg had an adjusted odds ratio for stroke of 1.3 (95% confidence interval 0.6 to 2.7). Those fairly well controlled (140-149 mm Hg), moderately controlled (150-159 mm Hg), or poorly controlled (> or = 160 mm Hg) or untreated had progressively raised odds ratios of 1.6, 2.2, 3.2, and 3.5 respectively. Results for diastolic pressure were similar; both were independent of initial pressures before treatment. Around 21% of strokes were thus attributable to inadequate control with treatment, or 46 first events yearly per 100,000 population aged 40-79. CONCLUSIONS: Risk of stroke was clearly related to quality of control of blood pressure with treatment. In routine practice consistent control of blood pressure to below 150/90 mm Hg seems to be required for optimal stroke prevention.     

Blood pressure and five year survival in the very old

During 1977-8 we measured blood pressure in 561 old people (83% of those aged 85 or more living in Tampere) and analysed their five year survival according to their blood pressure group. The subjects were divided into six groups on the basis of their blood pressures (from <120 to >200 mm Hg systolic, from <70 to >110 diastolic). The greatest mortality was observed in those in the lowest systolic and lowest diastolic groups. Mortality was least in subjects with systolic pressures of 160 mm Hg or more and diastolic pressures of 90 mm Hg or more.The most essential finding in this series of the very old was an increased mortality in the lowest blood pressure groups.     

Prospective cohort study of retinal vessel diameters and risk of hypertension

Objective To examine the relation between diameters of the retinal arterioles and 10 year incidence of hypertension.Design Population based prospective cohort study.Setting Beaver Dam eye study.Participants 2451 normotensive people aged 43 to 84 years.Main outcome measures Diameters of retinal arterioles and venules measured from digitised photographs of the retina taken at baseline. Measurements summarised as the arteriole:venule ratio, with a lower ratio indicating smaller arteriolar diameters. Incident hypertension, defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive drugs during follow up.Results 721 participants developed hypertension over a 10 year period. Those with lower arteriole:venule ratio had a higher cumulative incidence of hypertension (incidences of 17.4%, 24.1%, 31.0%, and 45.1%, respectively, for decreasing quarters of distribution of arteriole:venule ratio). After adjustment for age and sex, participants with arteriole:venule ratios in the lowest quarter had a threefold higher risk of hypertension (odds ratio 2.95, 95% confidence interval 2.77 to 3.88) than those with ratios in the highest quarter. This association remained significant after further adjustment for baseline systolic and diastolic blood pressure and other risk factors (1.82, 1.39 to 2.40, for lowest versus highest ratio quarters).Conclusions Narrowed retinal arterioles are associated with long term risk of hypertension, suggesting that structural alterations of the microvasculature may be linked to the development of hypertension.     

Community care compared with hospital outpatient care for hypertensive patients.

Three hundred and seventy-six patients with treated diastolic blood pressures of less than 105 mm Hg and no history of accelerated hypertension or renal failure were selected from among those attending the Hammersmith Hospital hypertension clinic. Their average lying treated blood pressure was 146 mm Hg systolic and 90 mm Hg diastolic and average age 56 years; 18% were black, 6% Asian, and 76% white. The patients were mostly having multiple treatment, 90% receiving a diuretic, 35% methyldopa, 33% propranolol, 18% atenolol, 9% hydrallazine, and 7% bethanidine. They were randomly allocated to either two years of further hospital outpatient care or referred back to their general practitioners. During the two years 19 (10%) of the 187 patients followed up in hospital defaulted and three had their treatment discontinued. Twelve (6%) of the 189 followed up by their general practitioners defaulted from follow-up and nine had their treatment discontinued. At the end of the trial the average lying blood pressure was 148 mm Hg systolic and 88 mm Hg diastolic in the hospital group and 149 mm Hg systolic and 90 mm Hg diastolic in the general practice group. The change in blood pressure was calculated for each individual and showed an average fall of 1.6 mm Hg in standing diastolic pressure in the hospital group and a rise of 1.4 mm Hg in the general practice group (p less than 0.05). The 90% confidence limits for a difference in standing diastolic pressure between the groups were 1 and 5 mm Hg with the pressure lower in the hospital group. General practice care was not quite as effective in controlling blood pressure as continued specialist supervision over two years in this selected group of treated outpatients with mild or moderate hypertension, but these results show that the discharge back to general practitioners of patients who are well controlled after hospital treatment is a sensible policy.     

Postural hypotension and diuretic therapy in the elderly.

Blood pressures were recorded in 319 ambulatory subjects, largely men, age 50 to 99 years. The mean systolic pressures were maximal in the seventh and eighth decades (136.0 and 132.1 mm Hg with the subjects supine and erect, respectively), whereas the mean diastolic pressures fell progressively after age 69. The distribution of postural changes in mean blood pressure was similar in each decade; a decrease of 20 mm Hg on more was noted in 3.4% of the subjects aged 80 to 99 years and in 4.1% of those aged 50 to 79 years. The frequency of postural hypotension was 4.6% in subjects treated with diuretics and 3.4% in those not so treated. Blood pressures and the frequency of postural hypotension did not progressively increase in age in this elderly population.     

Labetalol: potent antihypertensive agent that blocks both alpha- and beta-adrenergic receptors.

Labetalol was administered as the sole antihypertensive agent to 20 ambulatory patients with mild to moderate hypertension. The mean systolic and diastolic blood pressures (+/- standard error of the mean) with the patients sitting fell significantly (P < 0.001), from 145.5 +/- 3.2 and 103.7 +/- 1.6 mm Hg respectively at the start of labetalol therapy (after a period free of antihypertensive medication) to 125.7 +/- 2.0 and 87.2 +/- 1.1 mm Hg by the end of the trial. The diastolic blood pressure was well controlled (90 mm Hg or less) with labetalol therapy in 90% of the patients. The medication was well tolerated, and no orthostatic fall in the diastolic blood pressure was observed. Pharmacologically labetalol most closely resembles a combination of a nonselective beta-adrenergic blocker like propranolol and a postsynaptic alpha-adrenergic blocker like prazosin.     

Screen detected high blood pressure under 40: a general practice population followed up for 21 years.

OBJECTIVE--To assess hypertension detected under 40 in a general practice population. DESIGN--Prospective case-control study. SETTING AND SUBJECTS--Former coal mining community in south Wales. Systematic case finding for hypertension and associated risk factors applied to a mean total population of 1945 from age 20 on a five year cycle through 21 years. Mean population aged 20-39, 227 men and 213 women. Case criteria: age < 40 and mean systolic pressure > or = 160 mm Hg or diastolic pressure > or = 100 mm Hg. Age and sex matched controls randomly sampled from the same population. MAIN OUTCOME MEASURES--Mean initial pressures and pressures at follow up in 1989 or preceding death, and all cardiovascular events. RESULTS--25 men and 16 women met criteria. Estimated five yearly inceptions were 26/1000 for men and 18/1000 for women. Male group mean initial blood pressure was 164/110 mm Hg for cases, falling to 148/89 mm Hg at follow up. Five male cases died at mean age 47.8, compared with two controls at 49.5. Female group mean initial pressure was 172/107 mm Hg for cases, falling to 145/86 mm Hg at follow up. One female case died aged 50, no controls. 10 male cases had non-fatal cardiovascular events at mean age 40.2, compared with two controls at mean age 50.5. Four female cases had non-fatal events at mean age 47.2, compared with one control aged 58. Male differences were statistically significant. CONCLUSIONS--Hypertension under 40 is dangerous, commoner in men than women, rarely secondary to classic causes, and may be controlled in general practice on a whole community basis.     

Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials

Objective To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination.Design Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, β blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose.Subjects 40 000 treated patients and 16 000 patients given placebo.Main outcome measures Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs.Results All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, β blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose.Conclusions Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.     

Blood Pressure in Women Taking Oral Contraceptives

A controlled prospective survey of women taking oestrogen-progestogen oral contraceptives showed increases in mean systolic and diastolic blood pressure of 14·2 mm Hg and 8·5 mm Hg respectively after four years. The largest increases in individual cases were 36 mm Hg systolic and 20 mm Hg diastolic. Blood pressure returned to pretreatment levels within three months after oral contraceptives had been stopped. These changes in blood pressure were unrelated to the progestogenic potencies of the preparations being taken.     

Noise-induced hearing loss and blood pressure.

From a group of industrial workers who had a noise-induced hearing loss of at least 30 dB at 4000 Hz 62 were randomly selected after stratification. Controls matched for age and duration of employment were also selected. Resting blood pressures were measured and audiometry was repeated. The findings are presented by age group and for the two groups as a whole. No relation between systolic or diastolic blood pressure and hearing loss was found, and equal proportions of each group had blood pressures exceeding 140/90 mm Hg. Persons with greater hearing loss (more than 60 dB at 4000 Hz) did not have significantly higher blood pressures than their matched controls.     

Low blood pressure and dementia in elderly people: the Kungsholmen project.

OBJECTIVE--To examine the relation between blood pressure and dementia in elderly people. DESIGN--Cross sectional, population based study. SETTING: Kungsholmen district of Stockholm, Sweden. SUBJECTS-- 1642 subjects aged 75-101 years. MAIN OUTCOME MEASURES--Prevalence and adjusted odds ratio of dementia by blood pressure. RESULTS--People with systolic pressure < or = 140 mm Hg were more often diagnosed as demented than those with systolic pressure >140 mm Hg: odds ratios (95% confidence interval) adjusted for age, sex, and education were 2.98 (2.17 to 4.08) for all dementias, 2.91 (1.93 to 4.38) for Alzheimer''s disease, 2.00 (1.09 to 3.65) for vascular dementia, and 5.07 (2.65 to 9.70) for other dementias. Similar results were seen in subjects with diastolic pressure < or = 75 mm Hg compared with those with higher diastolic pressure. When severity and duration of dementia were taken into account, only moderate and severe dementia were found to be significantly related to relatively low blood pressure, and the association was stronger in subjects with longer disease duration. Use of hypotensive drugs and comorbidity with cardiovascular disease did not modify the results for all dementias, Alzheimer''s disease, and other dementias but slightly reduced the association between vascular dementia and diastolic blood pressure. CONCLUSIONS--Both systolic and diastolic blood pressure were inversely related to prevalence of dementia in elderly people. We think that relatively low blood pressure is probably a complication of the dementia process, particularly Alzheimer''s disease, although it is possible that low blood pressure may predispose a subpopulation to developing dementia.     

Blood Pressure Control with a Single-Pill Combination of Indapamide Sustained-Release and Amlodipine in Patients with Hypertension: The EFFICIENT Study

Objective

Despite antihypertensive treatment, most hypertensive patients still have high blood pressure (BP), notably high systolic blood pressure (SBP). The EFFICIENT study examines the efficacy and acceptability of a single-pill combination of sustained-release (SR) indapamide, a thiazide-like diuretic, and amlodipine, a calcium channel blocker (CCB), in the management of hypertension.

Methods

Patients who were previously uncontrolled on CCB monotherapy (BP≥140/90 mm Hg) or were previously untreated with grade 2 or 3 essential hypertension (BP≥160/100 mm Hg) received a single-pill combination tablet containing indapamide SR 1.5 mg and amlodipine 5 mg daily for 45 days, in this multicenter prospective phase 4 study. The primary outcome was mean change in BP from baseline; percentage of patients achieving BP control (BP<140/90 mm Hg) was a secondary endpoint. SBP reduction (ΔSBP) versus diastolic BP reduction (ΔDBP) was evaluated (ΔSBP/ΔDBP) from baseline to day 45. Safety and tolerability were also assessed.

Results

Mean baseline BP of 196 patients (mean age 52.3 years) was 160.2/97.9 mm Hg. After 45 days, mean SBP decreased by 28.5 mm Hg (95% CI, 26.4 to 30.6), while diastolic BP decreased by 15.6 mm Hg (95% CI, 14.5 to 16.7). BP control (<140/90 mm Hg) was achieved in 85% patients. ΔSBP/ΔDBP was 1.82 in the overall population. Few patients (n = 3 [2%]) reported side effects, and most (n = 194 [99%]) adhered to treatment.

Conclusion

In patients who were previously uncontrolled on CCB monotherapy or untreated with grade 2 or 3 hypertension, single-pill combination indapamide SR/amlodipine reduced BP effectively—especially SBP— over 45 days, and was safe and well tolerated.

Trial Registration

Clinical Trial Registry – India CTRI/2010/091/000114     

Control of blood pressure and risk of first acute myocardial infarction: Skaraborg hypertension project.

OBJECTIVE--To analyse the relation between treated blood pressure and concomitant risk factor and morbidity from acute myocardial infarction. DESIGN--Prospective longitudinal study. Treated blood pressures and other variables were used to predict acute myocardial infarction. SETTING--Primary health care in Skaraborg, Sweden. SUBJECTS--1121 men and 1453 women aged 40-69 years at registration at outpatient clinics, 1977-81, with no evidence of previous myocardial infarction were followed up for an average of 7.4 years. Subjects were undergoing treatment with drugs to lower blood pressure or had blood pressure that exceeded the systolic or diastolic limits, or both, for diagnosis (> 170/> 105 mm Hg (patients aged 40-60 years) and > 180/> 110 mm Hg (older than 60 years)) on three different occasions, or both. MAIN OUTCOME MEASURES--First validated event of fatal or non-fatal acute myocardial infarction. RESULTS--In men but not in women there was a negative relation between treated diastolic blood pressure and risk of acute myocardial infarction. Left ventricular hypertrophy and smoking were contributory risk factors in both sexes, as was serum cholesterol concentration in men. In men with normal electrocardiograms (n = 345) risk increased with increasing diastolic blood pressure (P = 0.047), whereas the opposite was found in men with electrocardiograms suggesting ischaemia or hypertrophy, or both (n = 499, P = 0.009). In those with a reading of 95-99 mm Hg the relative risk was 0.30 (P = 0.034); at > or = 100 mm Hg it was 0.37 (P = 0.027). No similar relations were seen in women or for systolic blood pressure. CONCLUSION--It may be hazardous to lower diastolic blood pressure below 95 mm Hg in hypertensive men with possible ischaemia or hypertrophy, or both. Electrocardiographic findings should be considered when treatment goals are decided for men with hypertension.     

Atenolol in essential hypertension during pregnancy.

OBJECTIVE--To determine the effect of atenolol on the outcome of pregnancy in women with essential hypertension. DESIGN--Prospective, randomised, double blind, placebo controlled study. SETTING--Hospital clinic. PATIENTS--33 Women with mild essential hypertension (systolic blood pressure 140-170 mm Hg or diastolic pressure 90-110 mm Hg on two occasions at least 24 hours apart) consecutively referred to two obstetric medical clinics. Four patients in the placebo group were withdrawn from the study: control of blood pressure was inadequate in two, one developed breathlessness, and one changed her mind about participating. The mean gestation in the 29 remaining women on entry to the study was 15.9 weeks. MAIN OUTCOME MEASURES--Blood pressure and birth weight. INTERVENTION--14 Women received placebo. 15 Women received atenolol 50 mg daily initially, increasing until either the blood pressure was less than 140/90 mm Hg or a dose of 200 micrograms daily was reached. RESULTS--The mean blood pressure on entry was 148/86 mm Hg in the group given atenolol and 144/86 mm Hg in the group given placebo. During treatment the mean diastolic pressure was significantly reduced by atenolol compared with placebo (to 74 v 81 mm Hg; difference in means (95% confidence interval) 7.0 (2.9 to 10.0) mm Hg) but the effect on systolic pressure was marginal (132 v 136 mm Hg; 4.0 (-1.4 to 8.6) mm Hg). Babies in the atenolol group had a significantly lower birth weight than those in the placebo group (2620 g v 3530 g; 910 (440 to 1380)g). CONCLUSION--Atenolol given from the end of the first trimester in patients with mild hypertension is associated with intrauterine growth retardation. When taken in conjunction with the results of a previous study in which methyldopa was given these findings indicate that benefit is unlikely to result from treating mild essential hypertension in pregnancy.     

Prevalence,Awareness and Control of Hypertension in Uganda

Background

Prevention and control of hypertension are critical in reducing morbidity and mortality attributable to cardiovascular diseases. Awareness of hypertension is a pre-condition for control and prevention. This study estimated the proportion of adults who were hypertensive, were aware of their hypertension and those that achieved adequate control.

Methods

We conducted a community based cross sectional survey among people≥15 years in Buikwe and Mukono districts of Uganda. People had their blood pressure measured and were interviewed about their social-demographic characteristics. Hypertension was defined as systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg, or previous diagnosis of hypertension. Participants were classified as hypertensive aware if they reported that they had previously been informed by a health professional that they had hypertension. Control of hypertension among those aware was if systolic blood pressure was <140 mmHg and diastolic blood pressure was <90 mmHg.

Results

The age standardized prevalence of hypertension was 27.2% (95% CI 25.9–28.5) similar among females (27.7%) and males (26.4%). Prevalence increased linearly with age, and age effect was more marked among females. Among the hypertensive participants, awareness was 28.2% (95% CI 25.4–31.0) higher among females (37.0%) compared to males (12.4%). Only 9.4% (95% CI 7.5–11.1) of all hypertensive participants were controlled. Control was higher among females (13.2%) compared to males (2.5%).

Conclusion

More than a quarter of the adult population had hypertension but awareness and control was very low. Measures are needed to enhance control, awareness and prevention of hypertension.     

The dilemma of isolated systolic hypertension.

Isolated systolic hypertension, characterized by elevated systolic blood pressure (greater than 150 to 165 mm Hg), normal diastolic blood pressure (less than 90 to 95 mm Hg) and, often, atherosclerosis, is now recognized as an important risk factor for cardiovascular disease. When the systolic pressure is 200 mm Hg or greater, or when it is 180 mm Hg or greater and accompanied by target organ damage, therapeutic intervention may be of value in patients under the age of 80 years. Low doses of thiazide diuretics have been shown to be safe and effective in lowering the systolic pressure. If the blood pressure remains high, treatment with methyldopa may be added.     

Binge Drinking and Blood Pressure: Cross-Sectional Results of the HAPIEE Study

Objectives

To investigate whether binge drinking pattern influences blood pressure independently from drinking volume or whether it modifies the effect of volume of drinking.

Methods

We used cross-sectional data from population samples of 7559 men and 7471 women aged 45–69 years in 2002-05, not on antihypertensive medication, from Russia, Poland and Czech Republic. Annual alcohol intake, drinking frequency and binge drinking (≥100 g in men and ≥60 g in women in one session at least once a month) were estimated from graduated frequency questionnaire. Blood pressure was analysed as continuous variables (systolic and diastolic pressure) and a binary outcome (≥140/90 mm Hg).

Results

In men, annual alcohol intake and drinking frequency were strongly associated with blood pressure. The odds ratio of high blood pressure for binge drinking in men was 1.62 (95% CI 1.45–1.82) after controlling for age, country, body mass index, education and smoking; additional adjustment for annual alcohol intake reduced it to 1.20 (1.03–1.39). In women, the fully adjusted odds ratio of high blood pressure for binge drinking was 1.31 (1.05–1.63). Binge drinking did not modify the effect of annual alcohol intake. Consuming alcohol as wine, beer or spirits had similar effects.

Conclusions

The results suggest that the independent long-term effect of binge drinking was modest, that binge drinking did not modify the effect of alcohol intake, and that different alcoholic beverages had similar effects on blood pressure.     

Effect of 3-year weight history on blood pressure: the atherosclerosis risk in communities study

The objective of this study was to examine the effect of weight history on blood pressure. Extant data from the Atherosclerosis Risk in Communities (ARIC) study were used to compare blood pressure in women (n=5,675) and men (n=4,893) with different 3-year weight histories, but similar current BMI. We used mixed models regression adjusted for ethnicity, age, education, field center, smoking, alcohol consumption, antihypertensive medications, interval length, and BMI at follow-up. We also examined associations between 3-year weight history and blood pressure within weight status categories (normal weight (>or=18.5 to <25.0 kg/m2), overweight (>or=25.0 to <30.0 kg/m2), and obese (>or=30.0 kg/m2)). We found weight history affected both systolic and diastolic blood pressures. Compared to men at the same BMI who had maintained their weight, men who had experienced a 10% weight gain over the previous 3 years had systolic and diastolic blood pressures that were 2.6 and 1.9 mm Hg higher, respectively (P<0.001 for both). Associations in women were in the same direction, but smaller at 0.9 and 0.6 mm Hg (P<0.001). With the exception of diastolic blood pressure in normal weight women, we found no significant interactions between weight change and current weight status. In conclusion, some of the variation in blood pressure among individuals at the same BMI may be due to weight change history. Effects of 3-year weight change history appear to be stronger and more consistent in men than in women, and generally similar regardless of current weight status.     

Controlled trial of biofeedback-aided behavioural methods in reducing mild hypertension.

Employees of a large industry were screened for the presence of coronary risk factors. A total of 204 employees, aged 35-64 years, with two or more such factors (serum cholesterol concentration greater than or equal to 6.3 mmol/l (243.6 mg/100 ml), blood pressure greater than or equal to 140/90 mm Hg, and current cigarette consumption greater than or equal to 10 cigarettes a day) were randomly allocated to a biofeedback group receiving training in relaxation and management of stress or a control group. Both groups received simple health education literature. After eight weeks of training, and again eight months later, the biofeedback group showed a significantly greater fall in systolic and diastolic blood pressures than the control group (p less than 0.001). Plasma renin activity and plasma aldosterone concentration were measured in a subsample at entry to the study and again at eight weeks and eight months; both showed a greater reduction in the biofeedback compared with the control group at eight weeks'' follow-up. The greater reduction in blood pressure in the subjects in the biofeedback group compared with the control group (11.0 mm Hg systolic and 8.8 mm Hg diastolic), persisting eight months after the training, suggests that relaxation-based behavioural methods might be offered as a first-time treatment to patients with mild hypertension.