The effects of glyceryl trinitrate, isosorbide dinitrate and sodium nitroprusside on haemodynamics, coronary blood flow and myocardial oxygen consumption - an experimental study.

The influences of glyceryl trinitrate, isosorbide dinitrate and sodium nitroprusside intravenously on haemodynamics, coronary circulation and myocardial oxygen consumption were investigated in closed chest dogs (n = 8). In an attempt to simulate heart failure the dogs received blood transfusion (15 ml/kg) in the presence of halothane-induced myocardial depression. All three nitrates reduced the loads for the left ventricle. With isosorbide dinitrate and sodium nitroprusside the preload and pulmonary pressure decreased to a greater extent than with glyceryl trinitrate. The haemodynamic results suggest that sodium nitroprusside is the favourable nitrate in left ventricular failure because it produces a balanced reduction in the ratio of pre- and afterload. Four micrograms/kg X min sodium nitroprusside induced marked coronary dilatation; glyceryl trinitrate had only a slight coronary vasodilating effect. With isosorbide dinitrate the myocardial blood flow remained well adapted to oxygen demand, the coronary vascular resistance did not change. Sodium nitroprusside produced a significant change of the transmural myocardial blood distribution-expressed as the epi/endocardial blood flow ratio. The ratio was increased by sodium nitroprusside, much more than by glyceryl trinitrate or isosorbide dinitrate.

Comparison of the immediate effects of etomidate, propanidid and thiopentone on haemodynamics, coronary bloodflow and myocardial oxygen consumption.

Since cardiovascular depression at induction is among the most common complications of anesthesia this comparative study was undertaken. Unpremedicated dogs (n = 16) were induced with 3 mg/kg piritramide i.v. and normoventilated (N2O/O2 = 2/1). In 8 animals 0.8 and 1.6 mg/kg Etomidate and 5.0 and 10.0 mg/kg thiopentone and in 8 further dogs 5.0 and 10.0 mg/kg Propanidid were tested. Equipotent doses of Thiopentone and Propanidid caused a marked myocardial depression, which was seen in a decrease in stroke volume and max dp/dt and in an increase of leftventricular end-diastolic pressure and pulmonary arterial pressure. The increased myocardial O2- cosumption mainly due to the rise in heart rate was covered after Thiopentone by an increase of coronary bloodflow (measured with a pitot-catheter) and an increase of arterio-coronaryvenous difference in oxygen. As the latter decreased after Propanidid, it appeared that Propanidid has coronary dilatory properties. The results demonstrated the uneconomic work of the heart under the influence of Thiopentone and Propanidid. In contrast to this the cardiovascular system after Etomidate remained nearly unaffected. The data of this study suggest the use of Etomidate rather than Thiopentone and Propanidid in cases of shock syndrome, heart and/or coronary insufficiency.

[Naloxone--a clinical study on dosage (author's transl)]. / Naloxon. (Eine klinische Untersuchung zur Frage der Dosierung).

In 50 Patients (group I) anaesthetized with neuroleptanalgesia and in 20 patients (group II) anaesthetized with moderate doses of fentanyl given to supplement nitrous oxide - halothane anaesthesia the postoperative respiratory depression was antagonized with naloxone. Each patient was carefully titrated with small increments of naloxone (40 microgram) given in 1-2 minute intervals. A reversal of the narcotic induced respiratory depression was taken for granted, when respiratory rate exceeded 12/min, tidal volume and blood gas analysis showed normal values. The results demonstrated a correlation between the need for naloxone and the time interval from the last administration of fentanyl to the completion of the operation and the fentanyl consumption per hour. When the interval was less than 1 hour more than 90% of the patients required postsurgical naloxone for respiratory inadequacy. The mean naloxone dose was 20 to 30% of the fentanyl dose given per hour: 1,2 microgram/kg naloxone reversed 4,9 microgram/kg.h fentanyl (group I) and 0,6 microgram/kg naloxone reversed 2,9 microgram/kg.h fentanyl (group II) respectively. To prevent renarcotization it is recommended to administer naloxone i.m. 30 to 45 min after the last naloxone-injection using the total i.v. dose.

[Experiences with continuous infusions of etomidate in cardiac surgery (author's transl)]. / Erfahrungen mit der Etomidate-Dauerinfusion in der Herzchirurgie

The hypnotic agent etomidate was added by infusion to a fentanyl-N2O-O2-anaesthesia for patients (n=15) requiring open heart surgery. The purpose of this procedure was to avoid awareness during operation (mean duration 187 min). The average amount of etomidate infused was 2.55 mg/kg, which seemed to be an overdose. The fentanyl consumption was slightly reduced as compared with a control group. No patients complained of awareness. The anaesthetic method studied is not thought to be superior to a high-dose fentanyl anaesthesia.

[Use of an electronic gravity infusion regulator for infusion therapy in routine conditions. Comparative clinical study]. / Einsatz eines elektronischen Schwerkraft-Infusionsreglers bei der Infusionstherapie auf Allgemeinstationen. Eine vergleichende klinische Untersuchung.

In comparison with the ordinary roller clamp the gravity-infusion controller allows a significant lowering of complications and start-ups at peripheral venous access sites. These results are effectively based on a decrease in the infiltration rate of about 30%. For approximately 80% of the remaining complications an early alarm and interruption of the infusion takes place. It is of importance that the electronic controller avoids the excessive variations of the drop rate found with roller clamps. In contrast to these advantages problems may arise under certain circumstances caused by the narrowing of the control range based on the limited available hydrostatic pressure. Application of the electronic gravity controller must be seen primarily for peripheral venous access sites. Its use is particularly advantageous where an infiltration of the infusion solution results in an endangering of the patient (cytostatic agents, strong alkaline solutions, for instance NaHCO3, potassium concentrates, medication additions, for instance vasoconstricting agents). In addition, it makes sense to use the controller in situations where the accuracy of an infusion regulated by a roller clamp is considered to be inadequate.

[Histamine H2-receptor blockade and thrombosis prophylaxis with heparin in tetanus. A case report (author's transl)]. / Histamin H2-Receptorenblockade und Thromboseprophylaxe mit Heparin beim Tetanus. Ein Fallbericht.

The use of "low-dose" heparin for the purpose of the prophylaxis of thrombosis is not yet general in the treatment of tetanus because this therapy may increase the risk of bleeding gastrointestinal stress-ulcers. The combination of heparin with histamine H2-receptor blockers, however, may be of therapeutic benefit and may reduce this complication as well as thrombosis. A case of tetanus and its therapy is reported.

[Artificial respiration of multi-injured patients with He-O2 and N2-O2 mixtures. II. Hemodynamics]. / Die Beatmung polytraumatisierter Patienten mit He-O2 und N2-O2-Gemischen.

Multi-injured patients (n = 18) requiring ventilatory support were alternatively ventilated with either He-O2 or N2-O2 mixtures (FiO2 = 0.3). Haemodynamic effects in favour of He-O2 were especially seen in cardiac output in arising PEEP. It was the result of a reduced intrathoracic pressure when administering He-O2 mixtures for controlled respiration. These results must be seen in combination with the advantages of the ventilatory effects.

[The cardiovascular effects of the inspiratory N2O-concentration during piritramide anaesthesia in the dog (author's transl)]. / Der Einfluss der inspiratorischen N2O-Konzentration auf das kardiovaskuläre System. Tierexperimentelle Untersuchungen in hochdosierter Piritramid-Basisnarkose.

Administration of nitrous oxide following large doses of narcotics has been reported to impair myocardial performance. In this investigation the effect of the inspiratory N2O-concentration (F1N2O = 0.0; 0.2; 0.4; 0.6; 0.8) upon haemodynamics, inotropism of the heart, coronary blood flow and myocardial oxygen consumption was studied in 8 dogs, which were normoventilated and narcotized with piritramide infused continuously (2.5 mg/kg-h). While 40% N2O(F1N2O = 0.4) decreased cardiac index (18%) and mean arterial pressure (5%) and increased total peripheral resistance (11%) significantly, the remaining inspiratory N2O-concentrations did not affect these parameters considerably. Load data, heart rate and the continuous decrease of LVdp/dtmax from 3170 mm Hg/s (F1N2O - 0.0) to 2175 mm Hg/s (F1N2O = 0.8) indicated negative inotropic properties of high concentrations of nitrous oxide. The myocardial oxygen demand, which was adequately met by the coronary blood flow, decreased with increasing N2O-concentrations initially by 18% (F1N2O = 0.4) due to bradycardia, slight hypotension and reduction in inotropism. Inhalation of 80% N2O, however, returned the energy demand of the heart to control levels (F1N2O = 0.0) resulting from increased myocardial wall-tension (increase in left ventricular end-diastolic pressure by 30%). The efficiency of left ventricular external work decreased from 18.6% (F1N2O = 0.0) to 14.7% (F1N2O - 0.8) indicating that myocardial performance was uneconomically influenced by high inspiratory N2O-concentrations and large doses of narcotics. The clinical implications of the results were discussed.

[Haemodynamic effect of naloxone during electrostimulation analgesia with special reference to the role of endorphin (author's transl)]. / Hämodynamische Untersuchung unter Naloxone während der Elektrostimulationsanalgesie (ESA) als Beitrag zur Endorphintheorie.

10 persons undergoing cardiac surgery in electro-stimulation analgesia (ESA) with controlled ventilation were given 5 microgram/kg bodyweight and 10 microgram/kg body-weight respectively of naloxone during the operation and the effects of the drug on the circulation were registered over a period of 10 minutes. The observations do not support the view that endorphin plays a part in ESA. Other possible modes of action are discussed.

[Respiration of multi-injured patients with He-O2 and N2-O2 mixtures. I. Ventilatory effects and pulmonary gas exchange]. / Die Beatmung polytraumatisierter Patienten mit He-O2-und N2-O2-Gemischen. I. Atemmechanik und pulmonaler Gasaustausch.

Polytraumatic patients (n = 19), requiring for ventilatory support [8, 23, 24], were alternatively normoventilated (PaCO2 approximately equal to 40 mm Hg) with either He-O2 or N2-O2 (FIO2 = 0,3) using positive endexspiratory pressures of 0, 5, 10 and 15 cm H2O. The results demonstrated that the tidal volume decreased by 17% during the ventilation with He-O2 as compared with N2-O2. At the same time the inspiratory resistance and the inspiratory peak-pressure decreased by 20%. These results can be explained by the physical properties of helium, since helium guarantees a laminar flow during respiration in contrast to N2 even in obstructive airways. In conclusion it can be said that polytrauma patients have a inhomogeneous distribution of ventilation starting at the day of accident, that leads to a rise in deadspace ventilation. Because of having lower respiration pressures by using He-O2 mixtures, pulmonary barotrauma could be reduced.

Effect of althesin on renal perfusion in anaesthetized dogs.

Since Althesin affects not only the systemic circulation but also certain regional blood flows autoregulated by intrinsic mechanisms, such as cerebral and coronary blood flow, the purpose of this study was to investigate the effect of Althesin upon renal blood flow. After an injection of 2.0 mg/kg Althesin, heart rate (63 per cent) and cardiac output (21 per cent) increased, while total peripheral resistance (25 per cent), mean aortic pressure (9 per cent) and the maximum rate of change of left ventricular pressure (31 per cent) decreased. In spite of the large renal fraction of cardiac output (17.4 per cent) the renal blood flow remained unchanged. Althesin is believed not to be contra-indicated in the presence of renal dysfunction.

[The effect of Fentanyl and Althesin on haemodynamics, inotropism of the heart and myocardial oxygen consumption in man (author's transl)]. / Die Wirkung von Fentanyl und Althesin auf die Hämodynamik, die Herzinotropie und den myokardialen Sauerstoffverbrauch des Menschen

The acute effect of Fentanyl and Althesin upon haemodynamics, inotropism of the heart and myocardial oxygen consumption has not been studied in man so far. Healthy premedicated pateints (n = 16) were lightly anaesthetized with nitrous oxide-oxygen (ratio 2:1), 0.3 Vol.-% forane and 0.3 Vol.-% halothane respectively. In order to avoid any interference with respiratory depression all subjects were normoventilated via an orotracheal tube. In a circulatory steady state a single dose of 0.01 mg/kg Fentanyl (n = 7) and 0.075 mg/kg Althesin (n = 9) respectively was injected intravenously within 20 sec. After the application of Fentanyl there was a delayed (5th min) fall in blood pressure by 23%, which was due to a reduction in total peripheral resistance (12%) and in cardiac output (thermodilution technique) by 13%. The decrease in cardiac output was the result of a bradycardia (18%). Considering heart rate, pre- and afterload simultaneously, the fall in max dp/dt (catheter-tip manometer) by 20% could not be explained as a decrease in myocardial contractility. The altered haemodynamics led to a decrease of the myocardial oxygen consumption (control 6.4 ml O2/min x 100 g) by 31%. The energy demand of the heart was quantitatively calculated using the formula of the complex haemodynamic parameter developed by Bretschneider. Immediately after the administration of Althesin the cardiac output rose on account of tachycardia slightly, while stroke volume (19%), total peripheral resistance (32%) and mean arterial pressure (24%) reacted reversely. Since heart rate increased (11%), preload remainded unchanged and afterload decreased, the fall in dp/dt max (20%) has to be understood as a moderate reduction in myocardial inotropism. The energy demand of the heart decreased only initially by 15%. The clinical implications of the results were discussed.

[The effects of the vasodilator nitroprusside on haemodynamics and myocardial oxygen consumption during drug induced myocardial depression (author's transl)]. / Kardiovaskuläre Wirkungen von Natriumnitroprussid während einer Myokarddepression.

The effect of the vasodilator nitroprusside (NP) on haemodynamics and myocardial oxygen consumption during drug induced myocardial oepression was examined in dogs (n = 7). The investigations were performed on closed chest dogs lightly anaesthetized with piritramide and N2O/O2 (ratio 2:1) under controlled ventilation and after beta-adrenergic blockade (1.5 mg/kg propranolol). After a loading dose and a continuous infusion of 0.3 mg/kg X min of pentobarbitone left ventricular maximum dp/dt was reduced to 50% of the control level, which was taken for granted as a standardized myocardial depression. Using an infusion of NP at a mean rate of 7 microgram/kg X min mean arterial pressure was then lowered to 80 mmHg for 20 min. The vasodilator therapy led to an increase in cardiac output and in stroke volume by 16%. Since the calculated endsystolic volume of the left ventricle decreased simultaneously (19%), the ejection fraction increased from 38% to 46%. There was also a significant reduction in left ventricular enddiastolic pressure (46%), which is supposed to result from the combined effects of an improved myocardial performance, a pooling of blood in peripheral vessels (indicated by decreases in enddiastolic volume by 6%, in mean pulmonary arterial pressure by 25% and in central venous pressure by 45%) and an increased ventricular compliance. Since the myocardial wall tension, a major determinant of myocardial energy demand, was lowered by increased ventricular compliance and reduced pre- and afterload, the oxygen consumption of the heart decreased by 22%. The smaller demand was supplied by an unchanged coronary blood flow. The narrowing of the a-v oxygen difference of the heart indicated a coronary dilatation (10%). The results obtained from this study support the clinical observations that NNP may improve an imbalanced ratio between myocardial oxygen supply and demand, in patients with impaired cardiac performance.

[Effect of high dosages of morphine and meperidine on haemodynamics, coronary blood flow and myocardial oxygen consumption in comparison to fentanyl and piritramide (author's transl)]. / Hämodynamik, Koronardurchblutung und myokardialer Sauerstoffverbrauch unter hohen Morphin-, Pethidin-, Fentanyl- und Piritromiddosen.

Although morphine is one of the oldest drugs known to man, it has only recently been used in large doses as an anesthetic agent. The main advantage is the cardiovascular stability. The purpose of this investigation was to study the circulatory response to high equianalgesic doses of morphine and meperidine. In 10 closed chest dogs during normoventilation and light background-anaesthesia (0.5 Vol. % halthane; N2O:O2 = 2:1) 2.0 mg/kg morphine and 15.0 mg/kg meperidine were given at random. Morphine produced a decrease in mean arterial blood pressure by 28%, which was paralleled by an identical fall in total peripheral resistance. No negative inotropic effects were found. In contrast to this, the severe hypotension developing with meperidine (decrease in blood pressure by 54%) was the result of peripheral vasodilatation (46%) and of myocardial depression indicated by a sharp drop in dp/dtmax (59%), dp/dtmax/IP (14%) and in left ventricular ejection fraction (33%). Utilizing the thermodilution technique, the cardiac output remained largely unaffected with both narcotic analgesics, as the increase in heart rate (morphine 27%; meperidine 101%) compensated for the fall in stroke volume (morphine 19%; meperidine 55%). In spite of the altered haemodynamics there was no change in the myocardial energy demand, which was adequately met by the coronary blood flow measured with the pressure-difference technique. Both, morphine and meperidine, produced initially an increase in coronary blood flow and coronary venous oxygen saturation indicating coronary vasodilation. While the mechanism for the change in cardiovascular status with high doses of morphine is vasodilatation probably due to histamine release, the results of this study suggest a peripheral as well as a central (myocardial depression) site of action with meperidine. The results obtained from this study were compared with the data from a previous investigation on equianalgesic doses of fentanyl and piritramide and their clinical implications were discussed.

Antagonism of morphine with naloxone in dogs: cardiovascular effects with special reference to the coronary circulation.

The cardiovascular effects of naloxone 15 microgram/kg following morphine 2.0 mg/kg were studied in closed-chest dogs during light nitrous oxide-halothane anaesthesia. The bolus injection of naloxone caused an increase in heart rate (73%), cardiac output (20%) and mean arterial pressure (20%). Total peripheral resistance was unaffected. LV dP/dt max and LV dP/dt max/IP increased by 25% and 14% respectively, but positive inotropic effects could not be shown when load data, heart rate and the decrease in left ventricular ejection fraction (22%) were taken into consideration. The cardiovascular stimulation resulted in an increase in myocardial oxygen demand (66%) which was met by an increase in coronary blood flow (59%). The data suggest that the antagonism of narcotics with high doses of naloxone may impair the myocardial oxygen supply in patients suffering from coronary insufficiency. It is concluded that naloxone should be titrated for each patient to ensure adequate reversal of respiratory depression and to avoid circulatory stress.

Effects of althesin, etomidate and fentanyl on haemodynamics and myocardial oxygen consumption in man.

The acute effects of althesin, etomidate and fentanyl upon haemodynamics, myocardial contractility and oxygen comsumption of the heart were studied in healthy premedicated patients (n = 15) lightly anaesthetized with N2O-O2 (ratio 2:1), 0.3 volumes per cent of halothane and isoflurane respectively. All individuals were ventilated at a normal level. The patients (n = 9) in the halothane group received etomidate 0.3 mg/kg and 20 minutes later althesin 0.075 ml/kg intravenously. In a second group of 6 patients on isoflurane fentanyl 0.01 mg/kg was given. Etomidate did not affect the cardiovascular system significantly. While the decrease in blood pressure after althesin (24 per cent) was the result of a reduction in total peripheral resistance (32 per cent), hypotension associated with fentanyl (23 per cent) was caused by diminished output due to bradycardia (18 per cent). Load data,heart rate, and maximum dp/dt indicated moderate negative inotropic properties only of althesin. Using the complex haemodynamic parameter developed by Bretschneider the myocardial oxygen consumption was calculated. The energy demand of the heart decreased with etomidate, althesin and fentanyl by 14 per cent, 16 per cent and 32 per cent respectively. It is concluded that the risk of cardiovascular depression at induction in patients with impaired myocardial performance and coronary insufficiency can be minimized with etomidate and/or fentanyl.

[The effect of ketamine on haemodynamics and myocardial oxygen consumption in anaesthetized dogs (author's transl)]. / Einfluss der Ketaminnarkose auf die Hämodynamik und den myokardialen Sauerstoffverbrauch narkotisierter Hunde

Ketamine is an induction agent. This experimental study was designed to investigate the immediate effects of ketamine upon haemodynamics, inotropism and myocardial oxygen consumption during induction. In a circulatory steady state of a piritramide - nitrous oxide - oxygen basic anaesthesia normoventilated dogs (n = 8) received intravenous injections of 5.0 and 10.0 mg/kg ketamine within 30 sec at random. Immediately after administration of 10.0 mg/kg ketamine the cardiac output (thermo dilution method) rose (27%) on account of tachycardia while the total peripheral resistance (40%) and the mean arterial pressure (23%) decreased. The decrease in stroke volume (37%) and the inotropic parameter dp/dt max (42%) as well as the increase in the end-diastolic left ventricular pressure (31%) and in the pressure of the pulmonary artery (11%) suggest considerable myocardial depressor properties of ketamine. The change in haemodynamics was paralleled with an increase in myocardial oxygen consumption (47%), which was initially met by an increase in coronary blood flow (25%) and an additional oxygen utilization (20%). The increase in arterio-coronary venous oxygen difference is believed to be due to a constriction of the coronary arteries after ketamine. Since external cardiac work remained unchanged,while myocardial contractility and myocardial wall tension (Psyst) decreased, the increase in heart rate (63%) explains the rise in myocardial oxygen consumption. The efficiency of cardiac work, which is defined as the ratio of myocardial displacement work to myocardial energy demand, decreased (31%) and illustrated the uneconomic work of the heart under the influence of ketamine. The clinical utilization of the data obtained from this study are discussed.

[Effect of high dosages of fentanyl and piritramide upon haemodynamics, coronary blood flow and myocardial oxygen consumption (author's transl)]. / Hämodynamik, Koronardurchblutung und myokardialer Sauerstoffverbrauch unter hohen Fentanyl- und Piritramiddosen

High dosages of narcotic analgesics are frequently utilized as the sole anaesthetic agents for patients requiring open-heart surgery. The purpose of this study was to investigate the effect of high dosages of fentanyl and piritramide upon the cardiovascular system. In anaesthetized dogs (N2O:O2=2:1; 0.5 vol% halothane) 0.03 mg/kg fentanyl (=8) and 1.5 mg/kg piritramide (n=8) respectively were given intravenously as a bolus. After the administration of fentanyl there was a slight decrease in blood pressure (10%). The hypotension was the result of a decrease in cardiac output (thermodilution technique) by 13% due to bradycardia. Total peripheral resistance and myocardial contractility remained unaffected. Similar effects were only found late after injection of piritramide, since there was an initial cardiovascular response to piritramide characterized by a marked fall in blood pressure (29%). The major cause of arterial hypotension was peripheral vasodilatation. Load data and the decrease in max dp/dt however indicated also a slight myocardial depression. The altered haemodynamics led to a decrease in myocardial oxygen consumption with both narcotics, which was nearly paralleled by a reduction in coronary blood flow. The narrowing of arteriovenous oxygen difference of the heart proved coronary dilatatory properties of fentanyl and especially of piritramide. This study indicated that high dosages of fentanyl have advantages in comparison to high dosages of piritramide. The clinical implications of the results are discussed.

Haemodynamics and myocardial oxygen consumption during isoflurane (forane) anaesthesia in geriatric patients.

The influence of isoflurane on haemodynamics and myocardial oxygen consumption was examined in seven geriatric patients under conditions of controlled ventilation and a normal arterial carbon dioxide tension. During isoflurane/nitrous oxide in oxygen anaesthesia (0.75 and 1.5 vol% inspired isoflurane) no significant changes occurred in cardiac output, stroke volume, heart rate, central venous and pulmonary artery pressure. Arterial pressure decreased, as did total peripheral resistance. A reduction in left ventricular maximum dp/dt (18-39%) was, at least in part, a result of changes in loading conditions. Total body (CaO2--CVO2) and base excess values remained within the normal range. We consider that the oxygen supply was adequate to meet the metabolic demands of the body as a whole. Myocardial oxygen consumption decreased by 25% during 0.75 vol% inspired isoflurane and by 43.5% with deepening of anaesthesia (1.5 vol% isoflurane).

[Effects of glucagon on systemic circulation, coronary blood flow and myocardial oxygen consumption in the anesthetized dog (author's transl)]. / Hämodynamik, Koronardurchblutung und Sauerstoffverbrauch des Herzens unter Glukagon. Untersuchungen am narkotisierten Hund

The systemic and coronary hemodynamic effects of 10, 20, 40 and 80 mug/kg glucagon have been studied in 9 anesthetized normoventilated closed-chest dogs. Intravenous administration of this agent produced a dose-related increase in the average coronary blood flow between 19% (10 mug/kg) and 49% (80 mug/kg). Coronary vascular resistance decreased by between 16% (10 mug/kg) and 39% (80 mug/kg). A--V O2 difference 1 min after the administration of glucagon no changes in myocardial oxygen extraction were observed after 5, 10 and 20 min. The calculated myocardial oxygen consumption rose up to 50% after 80 mug/kg glucagon. We conclude that the increase in coronary blood flow and the decrease in coronary resistance are mainly secondary to the metabolic effects of the increased myocardial contractility and heart rate, and that there is only an initial direct vasodilating effect on the coronary vessels.