Current Medical Research and Opinion (1996), 13, No. 7, 397-408

Gold Horizontal Line

The value of nifedipine in the treatment of hypertension, coronary heart disease and myocardial infarction (post-infarction therapy)

J. Schulz,*
J. Schmidt †
W. Rück ‡

*Ärztlicher Leiter Klinikum Buch, Wiltbergstr. 50, 13122 Berlin; Straußstr. 4, 01324 Dresden; Elsaßstr. 35, 44793 Bochum, Germany

Accepted: 19th December 1995

Gold Horizontal Line


Calcium antagonists are among the drugs most often prescribed in the treatment of cardiovascular diseases. Among the 2000 preparations most often prescribed in Germany in 1994, there were 48 calcium antagonists which presented a prescription rate of 1268 million defined daily doses.17 Calcium antagonists of the nifedipine type are by far the most often prescribed preparations of this group. They are targeted mainly against hypertension and coronary heart disease, with post-infarction angina pectoris also featuring among their indications. Recent publications5, 16 have, in consideration of indications on possible risks associated with nifedipine medication, fanned discussions on the pros and cons of nifedipine medication and thus the value of calcium antagonists in treating hypertension and CHD as well as post-infarction patients. The purpose of this report is to analyze the current situation and to draw conclusions for the practical use of calcium antagonists.

Key Words

Nifedipine - Hypertension - Coronary heart disease - Myocardial infarction

Arterial hypertension

Epidemiology and prognosis of hypertension

With a prevalence of approximately 20%, hypertension is the most frequent cardiovascular disease in Germany. The older a person, the more likely he or she suffers from hypertension. For men aged 30-39 years, the prevalence is approximately 15%, those aged 40-49 years, 23%, while the prevalence for men aged 50-65 years must be estimated at 30-35%. For women of the younger age groups, the probability of hypertension is lower and amounts to some 5% for those aged 30-39 years, and some 20-30% for those aged 50-65 years. For men and women over 65, the prevalence is more or less the same and amounts to approximately 50%, according to the findings of the STEPHY study.21

The main problem linked with hypertension is its risk potential. Since in most cases no symptoms are noticeable over long periods, the disease is often well established before treatment can be initiated. Currently some 25% of all causes of death must be reckoned to be associated with hypertension which was either not treated at all or inadequately treated, and this points to the importance of possible cardiovascular sequelae. A correlation between the degree of hypertension and mortality, as well as the emergence of severe cardiovascular complications, has been established.9, 11, 15 The organs most often affected are the heart, the brain and the kidneys, which, when affected by sequelae, predominantly cause the increased mortality. For instance, mortality in hypertensive patients with systolic blood pressure values of up to 170 mm Hg is already twice as high as that of normotensive subjects, while it is up to eight times higher if pressure values exceed 200 mm Hg. Likewise, increased diastolic blood pressure is associated with a rise in mortality (Figure 1). Thus, the 2-year survival rate in untreated malign hypertension amounts to some 10% only, and even in lower-degree hypertension with diastolic pressure values of 95-105 mm Hg, the yearly mortality rate of 45-year-old men is almost three times as high as that of normotensive subjects. The risk potential of hypertension is also demonstrated very clearly by the fact that a 35-year-old man presenting a blood pressure of 150/100 mm Hg, if untreated, is likely to die before the age of 60, which curtails his statistical life expectancy by 14 years.

Figure 1.
2-year-mortality in dependence on diastolic blood pressure. Adapted from data of G. W. Pickering15

The risk potential of hypertension is determined to a substantial degree by the presence of other cardiovascular risk factors.9 The more other risk factors there are, the higher the number of probable cardiovascular complications, and the higher the death rate. This has been proved convincingly by numerous studies. Beside hypertension, smoking and disturbed fat metabolism are two of the most important risk factors. Figure 2 shows the 5-year mortality rates caused by CHD in men aged 35-37 years, as found in the MRFIT study.10

Figure 2.
5-year-mortality in dependence on cardiovascular risk factors. Adapted from data of the Multiple Risk Factor Intervention Trial (MRFIT) 10 Ch = Cholesterol.

Prognosis for hypertension under efficient antihypertensive treatment

An effective treatment of hypertension, i.e. a therapy aimed at normalizing blood pressure, is able to decrease cardiovascular morbidity and mortality. This was proven in a number of convincing studies involving both quite young and elderly hypertensive patients; here, the incidence of strokes was reduced on average by 40% and that of myocardial infarction by 14%,7 although such findings have, so far, been generated only with respect to diuretics and/or beta blockers. For drugs belonging to these two groups, a reduction in cardiovascular morbidity and mortality could be established in young and old hypertensive patients. The first pertinent trials were carried out in the 1970s and early 1980s with thiazide diuretics which were at that time the first choice in treating hypertension. These studies showed a decrease in the number of severe complications associated with hypertension, such as cardiac or renal failure, severe hypertension and stroke, yet no reduction in the incidence of coronary heart disease.22 In the following years, investigations also included beta blockers which, at first, displayed an influence on morbidity and mortality similar and not superior to diuretics.10 In subsequent studies, beta blockers and diuretics reduced not only the overall mortality, but also the incidence of coronary heart disease (Figure 3).1, 2, 12, 20, 25 The HAPPHY study which investigated the efficacy of beta-blocker (metoprolol or atenolol) or diuretic treatment in young hypertensive patients with slight to moderate hypertension likewise showed that beta blockers and diuretics are equally efficacious in the long term.24 However, this study did not compare results with a placebo group. The MAPHY study not only confirmed the efficacy in reducing the overall cardiovascular mortality and the number of deaths related to sequelae of coronary heart disease when treating hypertensive patients aged 40-65 years, but also the superior efficacy of metoprolol as compared with thiazide diuretics.23

Figure 3.
Mean reduction of mortality and morbidity/1000 patients in 5 years in seven trials of diuretics in comparison to placebo. (VA II: Veterans Administration study II; EWPHE:European Working Party on High Blood Pressure in the Elderly; ANBP:Australian National Blood Pressure Study; USPH: U.S. Public Health Service Hospitals Study; MRC: Medical Research Council Study; Oslo-Study; HDFP 1: Stratum I of Hypertension Detection and Follow-up Programm Study

For a long time, it remained doubtful whether hypertensive patients over 60 would also benefit from an efficient antihypertensive therapy. To investigate this, corresponding studies using beta blockers and diuretics were performed with elderly hypertensive patients (> 60 years). The SHEP study showed that in patients over 60 with isolated systolic hypertension, i.e. the most frequent type of hypertension in elderly patients, treatment with diuretics and beta blockers significantly reduced cardiovascular morbidity and mortality with respect to the frequency of lethal and non-lethal strokes as well as the number of severe cardiovascular events.18 The STOP study investigated the treatment of diastolic hypertension in patients aged 70-84 years with a thiazide diuretic, a beta blocker (metoprolol or pindolol) as compared with a placebo group.3 In the verum groups, the effective decrease in blood pressure lowered the stroke risk by 47% and the risk of cardiovascular diseases by 40%. The frequency of myocardial infarction was altered only slightly (by 13%), while the number of cases of sudden cardiac death was reduced by 50% and the overall mortality by 43%.3 In the MRC study13 involving 4396 patients aged 65-74 years and suffering from diastolic hypertension, the treatment with beta blockers (atenolol) and/or thiazide diuretics (25 or 50 mg hydrochlorothiazide combined with 2.5 and 5 mg amilorid, respectively) reduced the cardiovascular risks. In the group treated with a beta blocker and a diuretic, the frequency of strokes could be reduced by 25% and that of coronary disorders by 19%. The incidence of all cardiovascular diseases was lowered by 17%. In the groups receiving one drug type only, the group treated with diuretics was superior to that given beta blockers, especially with respect to lowering cardiovascular risks.13

STONE study shows the prophylactic efficacy of nifedipine against hypertension in elderly patients

While studies so far limited themselves to the efficacy of diuretics and beta blockers in the long-term treatment of hypertension, we now have a first study on the efficacy of nifedipine in treating elderly hypertensive patients (60-74 years old).6 This trial (STONE study) verified the influence of a long-term treatment of 1632 patients suffering from essential hypertension with nifedipine compared to placebo. The study revealed a highly significant ( p < 0.001) reduction in the number of cases of stroke, cardiac failure, myocardial infarction, angina pectoris, severe dysrhythmia as well as the number of deaths and hospitalizations due to severe cardiovascular disorders (Figure 4). The decrease was particularly pronounced with respect to the number of strokes and cases of cardiac failure. The STONE study is the first trial to show an amelioration of the long-term prognosis for hypertensive patients treated with nifedipine, i.e. with a calcium antagonist.6

Summarizing these findings, a highly significant reduction in the overall mortality as well as cardiovascular morbidity and mortality is induced by beta blockers and diuretics in young as well as elderly hypertensive patients, and by nifedipine in elderly patients. This underlines the importance of an effective antihypertensive treatment to prevent cardiovascular complications associated with hypertension.

Does long-term treatment with nifedipine increase the incidence of myocardial infarction in hypertensive patients?

The findings recently published by B. M. Psaty et al.16 caused some unrest and apprehension as to the most suitable hypertensive treatment. They reported on a retrospective case-control study comparing the data of hypertensive patients who had suffered myocardial infarction (cases) with the data of hypertensive patients without myocardial infarction (controls).
Figure 4.
Prevention of severe complications of hypertension in elderly subjects.
Adapted from data of the STONE-study 6

The analysis of the treatment administered to 291 cases who suffered a myocardial infarction during the observation period, and to 1240 controls (without myocardial infarction), compared with hypertensive patients treated with diuretics (relative risk, rr = 1), showed a relative risk of 1.08 for beta blockers, 1.07 for ACE inhibitors and 1.25 for calcium antagonists (Table I). These differences were non-significant, i.e. none of the treatment groups differed significantly from the group treated with diuretics with respect to the infarction rate. There was only one sub-group of hypertensive patients treated with high doses of calcium antagonists or a combination of high-dosage calcium antagonists and diuretics who presented a significantly increased relative risk. Unfortunately, the information available so far on this issue does not include details on the dosage used. Furthermore, the various calcium antagonists used were pooled. This study and the conclusions deducted from it were rightly criticised by renowned cardiologists. From the available data, it may not be concluded that hypertensive patients under mono-therapy with calcium antagonists are more at risk of suffering myocardial infarction than those treated with diuretics, beta blockers or ACE inhibitors. When considering the numerous study results showing the benefits of an antihypertensive treatment using diuretics and beta blockers in reducing the risk of acquiring and dying of severe cardiovascular complications, seeing that the treatment with calcium antagonists or ACE inhibitors does not significantly differ from that with diuretics, it may be reckoned that calcium antagonists may also have a positive effect. The findings indicating that the risk might possibly be higher with nifedipine preparations characterized by a quick onset, but short action (dosage > 80 mg/day), as they are predominantly used in the USA, are not applicable as they are to the situation in Germany. Here, the majority of preparations used are slow-release formulations administered in dosages of 2 × 20 mg or 1 × 30-50 mg per day. Moreover, the retrospective American statements should be verified in controlled prospective studies.

Table I
Mortality risk in trials of different antihypertensive therapies
Antihypertensive drugs Risk ratio
Beta-Blockers 1.08 (0.70-1.66)
ACE-inhibitors1.07 (0.65-1.80)
Calcium antagonists 1.25 (0.78-1.98)

Adapted from Psaty et al.16

Coronary heart disease

Another important field of application for calcium antagonists are the various types of angina pectoris. The successful treatment of angina pectoris with nifedipine preparations is documented on a world-wide scale by well-founded controlled clinical trials whose results have been confirmed a million times in practice. Indisputably, vasospastic angina (Prinzmetal's or variant angina) and chronic, stable angina (exertion angina) feature among the indications for calcium antagonists, with nifedipine being by far the best investigated and most often prescribed active substance world-wide. The use of calcium antagonists in treating unstable angina, however, must be judged with more caution. This disease is most often treated with nitrates, mainly combined with antithrombotic agents and platelet aggregation inhibitors. In cases where this therapy shows no sufficient effect, beta blockers are recommended, either alone or associated with the above preparations. In such cases, calcium antagonists should not be used as a matter of routine. Individual case reports point to a possible deterioration in the picture of unstable angina and even to an increased probability of myocardial infarction. Therefore, calcium antagonists should be used in unstable angina only under close medical supervision.

The recently much cited report published by Furberg et al.5 which contained a meta-analysis of 16 randomized clinical studies including three trials involving patients with unstable angina pectoris, claims that nifedipine preparations with quick onset and short action given in a daily dosage of > 60 mg increased the mortality risk. While a daily dosage of 30-60 mg did not enhance mortality as compared with the control group, patients given a daily dosage of 80 or > 100 mg nifedipine had an increased mortality risk (Table II). In Germany, however, slow-release preparations displaying a gradual onset of action are usually used. This underlines that the preparations and dosages usually administered in Germany to patients with unstable angina pectoris involve no increased mortality risk. The claims that high-dosage, fast-acting nifedipine preparations are associated with an increased mortality risk should be verified in further targeted, prospective studies; they emphasize that calcium antagonists of the dihydropyridine type should be used with caution in unstable angina pectoris. When judging the results of Furberg et al.,5 it must be taken into account that the type of meta-analysis performed has been strongly criticized by leading cardiologists. Numerous mistakes in grouping the patients covered by retrospective analysis as well as the fact that patients in the control group received varying treatment, also with beta blockers, qualify the claim of an increased relative risk.

Table II.
Mortality risk in trials of nifedipine in myocardial infarction and unstable angina (Furberg et al.5)
DosageRisk ratio
30 mg/day1.01
40 mg/day1.09
50 mg/day1.03
60 mg/day1.18
80 mg/day2.83
> 100 mg/day2.20

Acute myocardial infarction

In the treatment of acute myocardial infarction, the use of calcium antagonists is not recommended. This is stated also in the expert information on nifedipine products. A positive influence on the acute infarction process, which had originally been expected based on findings in animal trials, could not be backed up with clinical results. Beta blockers and, as most recent study results show, ACE inhibitors such as captopril or lisinopril have acquired more importance in this respect.

Secondary prevention of myocardial infarction

Calcium antagonists can be used to treat post-infarction angina, although starting only 8-14 days after the acute event and respecting the indications for angina pectoris. With respect to a possible secondary prevention of myocardial infarction, however, the situation is more complex. The effects of the three calcium antagonists nifedipine, verapamil and diltiazem are all different.

For dihydropyridines, and thus for calcium antagonists of the nifedipine type, no evidence of an effective secondary preventive action has been generated so far. The studies available in this respect show no reduction in cardiovascular mortality or in the rate of recurrent infarction, indicating on the contrary even a slightly, though non-significantly, increased risk of recurrent infarction and mortality. Dihydropyridines therefore should be recommended for the treatment of post-infarction angina, but not for secondary prevention of myocardial infarction. The possibly increased risk of recurrent infarction and mortality must be further investigated in more detailed trials. In this context, the meta-analysis published by Furberg et al.,5 should be taken into account. They analysed the results of 16 randomized clinical studies, including 12 trials in patients having suffered myocardial infarction, using short-acting nifedipine preparations in a dosage of 30-120 mg/day. When considering all patient data, the nifedipine group presented a slightly increased relative risk (rr = 1.16). When breaking down the data according to dose-effect relations, patients given nifedipine in a dosage of 30-50 mg/day had no increased mortality risk. The dosage of 60 mg/day involved a relative risk of 1.18 and thus a trend towards an increased mortality. Patients given doses of 80 and > 100 mg/day had a relative risk of 2.83 and 2.20, respectively, and thus a clearly increased mortality risk as compared with the control group or with patients receiving 30-50 mg/day (Table II). Even if, owing to the limited meaningfulness of this meta-analysis, no rash conclusions as to the use of nifedipine preparations should be drawn, these results confirm that nifedipine in this presentation form (fast onset, short duration of action) is not suitable for the prevention of myocardial infarction, and they call for caution in using these preparations in high doses when treating post-infarction patients. It must be taken into account that beta blockers, and now some ACE inhibitors, have been proven efficiently to prevent secondary myocardial infarction, so these preparations should certainly be given preference when treating post-infarction patients.

The situation is slightly different with respect to verapamil and diltiazem. Verapamil was investigated in two rather extensive studies (DAVIT-I and DAVIT-II). The DAVIT-I study involved 3500 patients with established or suspected myocardial infarction who were treated with verapamil for 6 months. When compared with a control group, no decrease in mortality was found,4 while retrospective analysis revealed a tendency towards a reduced mortality after 4 weeks. In the DAVIT-II study, the verapamil treatment was initiated only 1-3 weeks after the onset of the infarction and carried on for a period of 16 months.19 In this study, the number of deaths could be reduced from 116 of 897 patients in the placebo group to 95 of 878 patients in the verapamil group. When considering all data available on verapamil, a slight decrease in mortality of 9% was proven without being backed up by statistics. Moreover, there was a clear-cut reduction in the number of recurrent infarctions which amounted to 171 of 2624 patients in the placebo group, yet to only 138 of 2606 patients treated with verapamil.

In the studies available for diltiazem, no reduction in cardiovascular mortality in post-infarction patients was found.14 A sub-group analysis, however, revealed a much more complex picture depending on the overall clinical situation connected with the infarction. For instance, patients without pulmonal congestion who received diltiazem showed a lower cumulative rate of cardiac events (8%) than those under placebo, while patients with pulmonal congestion developed more cardiac disorders when treated with diltiazem (26%) than those given placebo (18%). Patients with an ejection fraction of > 40% as well as patients with non-Q-wave infarction benefitted from diltiazem medication. These patients of the diltiazem group showed a clearly reduced number of cardiac events as compared with those from the placebo group.


An effective antihypertensive treatment should do more than just normalize blood pressure and should therefore always be subject to careful observation of the concomitant diseases and cardiovascular risk factors which the individual patient presents. Moreover, evaluating the effects of the therapy chosen on the patient's long-term prognosis is becoming an increasingly important feature. In this context, it becomes obvious that none of the groups of antihypertensive agents currently in use is able to comply with all requirements demanded of an 'ideal' antihypertensive drug, while each of the individual drug groups show specific peculiarities, allowing hypertensive patients with varying concomitant diseases and cardiovascular risk factors to be treated in various different ways. The increasingly conscious, effective implementation of such differential therapy is an essential prerequisite for successful antihypertensive treatment and thus for primary and secondary prevention of its severe cardiovascular complications. In this respect, calcium antagonists constitute an important, indispensible group of antihypertensive agents. They effectively lower blood pressure and exert a number of favourable secondary effects aimed against frequent diseases typically associated with hypertension (Table III). There is no reason why this proven, time-tested group of drugs should be denied to hypertensive patients. The STONE study evidences the positive effects of a long-term antihypertensive treatment with nifedipine on elderly hypertensive patients. For the first time, a reduction in the frequency of cardiovascular complications could thus be proven also for nifedipine, albeit so far only for elderly hypertensive patients. Further studies should clarify whether preparations with fast onset of action in high dosages (> 60 mg/day) actually have a comparatively unfavourable influence on cardiovascular risks.

Table III.
Positive effects of nifedipine in concomitant diseases of hypertension
EffectBenefit by
VasospasmolyticCHD, pAOD, TIA
Improvement of peripheral blood flow pAOD
BronchodilatativeObstructive respiratory diseases
NephroprotectiveDiabetic nephropathia
Regression of left ventricular hypertrophia Left ventricular hypertrophia
Inhibition of progression of atherosclerosis Atherosclerosis
Rheological effects (inhibition of aggregation) CHD, pAOD, TIA

Indisputably, calcium antagonists are important in treating chronic stable angina pectoris (exertion angina) and vasospastic angina (Prinzmetal's angina or variant angina). In unstable angina pectoris, calcium antagonists should be used only in strictly limited indications and not as first choice. In these cases, high-dosage nifedipine preparations with fast onset of action should be administered only after carefully weighing-up the risks and benefits and, whenever possible, in combination with a beta blocker.

Calcium antagonists are not recommended for treating acute myocardial infarction (cf. also expert information on the preparations).

In the post-infarction phase, calcium antagonists may be administered starting in the first or second week after the onset of the infarction to treat stable post-infarction or vasospastic angina pectoris. In the treatment of unstable angina following myocardial infarction, the above restrictions must be observed. Secondary prevention of myocardial infarction is, according to the current state of knowledge, not achievable with calcium antagonists of the nifedipine type. In these cases, beta blockers and ACE inhibitors (e.g. lisinopril) should be used in preference. In contrast to nifedipine preparations, verapamil and diltiazem may possibly reduce the frequency of recurrent infarction.


1. Andersson, O. et al., (1978). Organization and efficacy of an out-patient hypertension clinic. Acta Med. Scand., 203, 391-398.

2. Berglund, G. et al., (1978). Coronary heart disease after treatment of hypertension. Lancet 1, 1-5.

3. Dahlöf, B. et al., (1991). Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-hypertension). Lancet, 338, 1281-1285.

4. Danish Study Group on Verapamil in Myocardial Infarction, (1988). Verapamil in acute myocardial infarction. Eur. Heart J., 5, 516-528.

5. Furberg, C. D. et al., (1995). Nifedipine, dose-related increase in mortality in patients with coronary heart disease. Circulation, 92, 1326-1331

6. Gong, L. et al., (1995). Shanghai trial of nifedipine in the elderly (STONE), Abst.298, 7th European Congress on Hypertension. Intern. Med. World Report, 10, 30

7. Hebert, P. R. et al., (1993). Commentary: recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease. Arch. Intern. Med., 153, 578-581.

8. Held, P. H. and Yusuf, S., (1993). Effects of Beta-blockers and calcium channel blockers in acute myocardial infarction. Eur. Heart J., 14, 18-25.

9. Kannel, V. B. (1974). Role of blood pressure in cardiovascular morbidity and mortality. Prog. Cardiovasc. Dis., 17, 5-25.

10. MacMahon, S. W. et al. for the Multiple Risk Factor Intervention Trial Research Group, (1986). Relationship of blood pressure to coronary and stroke morbidity and mortality in clinical trial and epidemiological studies. J. Hypertension, 2, 586-593.

11. Marmot, M. G., (1986). Epidemiology and the art of the soluble. Lancet, i, 197-200.

12. Medical Research Council Working Party (MRCWP) on Mild to Moderate Hypertension, (1981). Adverse Reactions to Bendrofluazide and Propranolol for the Treatment of Mild Hypertension. Lancet, 2, 539-543.

13. MRC Working Party, (1992). Medical Research Council Trial Treatment of Hypertension in Older Adults: Principal Results. Brit. Med. J., 304, 405.

14. Multicenter Diltiazem Postinfarction Trial Research Group, (1988). The effect of diltiazem on mortality and reinfarction after myocardial infarction. N. Engl. J. Med., 319, 385-392.

15. Pickering, G. W., (1968). High Blood Pressure, Churchill, London. 2nd edn.

16. Psaty, B. M. et al., (1995). The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA, 274, 620-625.

17. Schwabe, U. and Paffrath, D., (1995). Arzneiverordnungs-Report '95, Gustav Fischer Verlag, Stuttgart, Jena.

18. Shep Cooperative Research Group, (1991). Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA, 265, 3255-3264.

19. The Danish Study Group on Verapamil in Myocardial Infarction, (1990). Effect of Verapamil on Mortality and Major Events after Acute Myocardial Infarction (The Danish Verapamil Infarction Trial II - DAVIT II). Am J. Cardiol., 66, 779-785.

20. The IPPPSH Collaborative Group, (1984). The International Prospective Primary Prevention Study in Hypertension (IPPPSH): Objectives and methods, Eur. J. Clin. Pharmacol., 27, 379-391.

21. Trenkwalder, P. et al., (1994). Kardiovaskuläre Risikofaktoren bei über 65jährigen in Deutschland, Ergebnisse der STEPHY-Studie (Starnberg Trial on Epidemiology of Parkinsonism and Hypertension in the Elderly). Z. Kardiol., 83, 830-839.

22. Wikstrand, J., (1986). Initial therapy for mild hypertension. Pharmacotherapy, 6, 64-72.

23. Wikstrand, J., (1988). Primary prevention with metoprolol in patients with hypertension. Mortality results from the MAPHY study. JAMA, 259, 1976-1982.

24. Wilhelmsen, L. et al., (1987). Beta-blockers versus diuretics in hypertensive men: Main results from the HAPPHY trial. J. Hypertension, 5, 561-572.

25. Wilhelmsen, L., (1981). Beta-Blockers versus saluretics in hypertension: Comparison of total mortality, myocardial infarction and sudden death: Study design and early results on blood pressure reduction. Prev. Med., 10, 38-49.