Clinical effects of thigh cuffs during a 7-day 6 degrees head-down bed rest.

Thigh cuffs are used by Russian cosmonauts to limit the fluid shift induced by space flight. A ground simulation using the head-down bed rest (HDBR) model was performed to assess the effects of thigh cuffs on clinical tolerance and orthostatic adaptation. 8 male healthy volunteers (32.4 +/- 1.9 years) participated twice in a 7-day HDBR--one time with thigh cuffs (worn daily from 9 am to 7 pm) (TC) and one time without (WTC). Orthostatic tolerance was assessed by a 10 minute stand test and by a LBNP test (5 min at -15, -30, -45 mmHg) before (BDC-1) and at the end of the HDBR period (R+1). Plasma volume was measured before and at the end of HDBR by the Evans blue dye dilution technique. Thigh cuffs limits headache due to fluid shift, as well as the loss in plasma volume (TC: -5.85 +/- 0.95%; WTC: -9.09 +/- 0.82%, p<0.05). The mean duration of the stand test (R+1) did not differ in the two group (TC 7.1 +/- 1.3 min; WTC 7.0 +/- 1.0 min). The increase in HR and decrease in diastolic blood pressure were slightly but significantly larger without thigh cuffs. Duration of the LBNP tests did not differ with thigh cuffs. Thigh cuffs limit the symptoms due to fluid shift and the loss in plasma volume. They partly reduced the increase in HR during orthostatic stress but had no effect on duration of orthostatic stress tests.     

Central and regional hemodynamics in prolonged space flights.

This paper presents the results of measuring central and regional (head, forearm, calf) hemodynamics at rest and during provocative tests by the method of tetrapolar rheography in the course of Salyut-6-Soyuz and Salyut-7-Soyuz missions. The measurements were carried out during short-term (19 man-flights of 7 days in duration) and long-term (21 man-flights of 65-237 days in duration) manned missions. At rest, stroke volume (SV) and cardiac output (CO) as well as heart rate (HR) decreased insignificantly (in short-term flights) or remained essentially unchanged (in long-term flights). In prolonged flights CO increased significantly in response to exercise tests due to an increase in HR and the lack of changes in SV. After exercise tests SV and CO decreased as compared to the preflight level. During lower body negative pressure (LBNP) tests HR and CO were slightly higher than preflight. Changes in regional hemodynamics included a distinct decrease of pulse blood filling (PBF) of the calf, a reduction of the tone of large vessels of the calf and small vessels of the forearm. Head examination (in the region of the internal carotid artery) showed a decrease of PBF of the left hemisphere (during flight months 2-8) and a distinct decline of the tone of small vessels, mainly, in the right hemisphere. During LBNP tests the tone of pre- and postcapillary vessels of the brain returned to normal while PBF of the right and left hemisphere vessels declined. It has been shown that regional circulation variations depend on the area examined and are induced by a rearrangement of total hemodynamics of the human body in microgravity. This paper reviews the data concerning changes in central and regional circulation of men in space flights of different duration.     

Effect on the cardiac function of repeated LBNP during a 1-month head down tilt

Cardiovascular assessment by ultrasound methods was performed during two long duration (1 month) Head Down Tilt (HDT) on 6 healthy volunteers. On a first 1 month HDT session, 3 of the 6 subjects (A, B, C) had daily several lower body negative pressure tests (LBNP), whereas the 3 subjects remaining (D, E, F) rested without LBNP. On a second 1 month HDT session subjects D, E, and F had daily LBNP tests and the A, B and C subjects did not. The cardiac function was assessed by Echocardiography, (B mode, TM mode). On all the "6 non LBNP" subjects the left ventricule diastolic volume (LVDV), the stroke volume (SV) and the cardiac output (CO) increase (+10%, -15%) after HDT then decrease and remain inferior (-5%, -5%) or equal to the basal value during the HDT. Immediately after the end of the HDT the heart rate (HR) increase (+10%, +30%) whereas the cardiac parameters decrease weakly (-5%, -10%) and normalize after 3 days of recovery. On the "6 LBNP" subjects the LVDV, SV and CO increase (+10%, 15%) after 1 h HDT as in the previous group then decrease but remain superior (+5%, +15%) or equal to the basal value. After the HDT session, the HR is markedly increased (+20%, +40%) the LVDV and SV decrease (-15%, -20%) whereas the CO increases or decreases depending on the amplitude of the HR variations. These parameters do not completely normalize after 3 day's recovery. Repeated LBNP sessions have a significant effect on the cardiovascular function as it maintains all cardiac parameters above the basal value. The LBNP manoeuvre can be considered as an efficient countermeasure to prevent cardiac disadaptation induced by HDT position and probably microgravity.     

Preliminary application of a novel algorithm to monitor changes in pre-flight total peripheral resistance for prediction of post-flight orthostatic intolerance in astronauts

Orthostatic intolerance (OI) is a significant challenge for astronauts after long-duration spaceflight. Depending on flight duration, 20–80% of astronauts suffer from post-flight OI, which is associated with reduced vascular resistance. This paper introduces a novel algorithm for continuously monitoring changes in total peripheral resistance (TPR) by processing the peripheral arterial blood pressure (ABP). To validate, we applied our novel mathematical algorithm to the pre-flight ABP data previously recorded from twelve astronauts ten days before launch. The TPR changes were calculated by our algorithm and compared with the TPR value estimated using cardiac output/heart rate before and after phenylephrine administration. The astronauts in the post-flight presyncopal group had lower pre-flight TPR changes (1.66 times) than those in the non-presyncopal group (2.15 times). The trend in TPR changes calculated with our algorithm agreed with the TPR trend calculated using measured cardiac output in the previous study. Further data collection and algorithm refinement are needed for pre-flight detection of OI and monitoring of continuous TPR by analysis of peripheral arterial blood pressure.     

Skylab experiment M-092: results of the first manned mission

Blood pressure at 30-sec intervals, heart rate, and percentage increase in leg volume continuously were recorded during a 25-min protocol in the M092 Inflight Lower Body Negative Pressure (LBNP) experiment carried out in the first manned Skylab mission. These data were collected during six tests on each crewman over a 5-month preflight period. The protocol consisted of a 5-min resting control period, 1 min at -8, 1 min at -16, 3 min at -30, 5 min at -40, and 5 min at -50 mm Hg LBNP. A 5-min recovery period followed. Inflight tests were performed at approximately 3-day intervals through the 28-day mission. Individual variations in cardiovascular responses to LBNP during the preflight period continued to be demonstrated in the inflight tests. Measurements of the calf indicated that a large volume of fluid was shifted out of the legs early in the flight and that a slower decrease in leg volume, presumably due to loss of muscle tissue, continued throughout the flight. Resting heart rates tended to be low early in the flight and to increase slightly as the flight progressed. Resting blood pressure varied but usually was characterized by slightly elevated systolic blood pressure, lower diastolic pressure, and higher pulse pressures than during preflight examinations. During LBNP inflight a much greater increase in leg volume occurred than in preflight tests. Large increases occurred even at the smallest levels of negative pressure, suggesting that the veins of the legs were relatively empty at the beginning of the LBNP. The greater volume of blood pooled in the legs was associated with greater increases of heart rate and diastolic pressure and larger falls of systolic and pulse pressure than seen in preflight tests. The LBNP protocol represented a greater stress inflight, and on three occasions it was necessary to stop the test early because of impending syncopal reactions. LBNP responses inflight appeared to predict the degree of postflight orthostatic intolerance. Postflight responses to LBNP during the first 48 hours were characterized by marked elevations of heart rate and instability of blood pressure. In addition, systolic and diastolic pressures were typically elevated considerably both at rest and also during stress. The time required for cardiovascular responses to return to preflight levels was much slower than in the case of Apollo crewmen.     

Effect of the thigh-cuffs on the carotid artery diameter jugular vein section and facial skin edema: HDT study.

Objective: To evaluate the distal arterial, venous and skin changes in a group using thigh cuffs during daytime and in a control group. Method: Cardiac, arterial, venous parameters were measured by echography and Doppler. Skin thickness was measured by high frequency echography. Results & discussion: Head down position induced plasma volume reduction, increased cerebral resistance, reduced lower limb resistance. The jugular vein increased whereas the femoral and popliteal veins decreased. All these changes were already observed in previous HDT. Common carotid diameter decreased, Front head skin thickness increased and Tibial skin thickness decreased. Eight hours with thigh cuffs increased the cardiac and carotid sizes which is in agreement with the plasma volume increase. Conversely they reduced the cerebral vascular resistance, jugular section and front head edema which may explain the sensation of comfort reported by the subjects. At the lower limb level the thigh cuffs restored the skin thickness to pre-HDT level but enlarged markedly the femoral and popliteal veins. HR, BP, CO, TPR did not change.     

The human cardiovascular system during space flight

Purpose of the work is to analyze and to summarize the data of investigations into human hemodynamics performed over 20 years aboard orbital stations Salyut-7 and Mir with participation of 26 cosmonauts on space flights (SF) from 8 to 438 days in duration. The ultrasonic techniques and occlusive plethysmography demonstrated dynamics of changes in the cardiovascular system during SF of various durations. The parameters of general hemodynamics, the pumping function of the heart and arterial circulation in the brain remained stable in all the space flights; however, there were alterations in peripheral circulation associated with blood redistribution and hypovolemie in microgravity. The anti-gravity distribution of the vascular tone decayed gradually as unneeded. The most considerable changes were observed in leg vessels, equally in arteries (decrease in resistance) and veins (increase in maximum capacity). The lower body negative pressure test (LBNP) revealed deterioration of the gravity-dependent reactions that changed for the worse as SF duration extended. The cardiovascular deconditioning showed itself as loss of descent acceleration tolerance and orthostatic instability in the postflight period.     

Cardiovascular reflexes during rest and exercise modified by gravitational stresses.

The hypotheses tested were whether variations in central venous pressure via the low pressure baroreceptors would take over or modify the arterial baroreceptor function, and further to which extent local and "whole body" hydrostatic stresses influence blood flow distribution. We investigated total forearm and skin blood flow (venous occlusion plethysmography and 133-Xe clearance) and cardiac output (rebreathing method) among other parameters. Hypo- and hyper-gravitational stresses were simulated by LBNP, LBPP, water immersion and lowering of the arm. The changes in flow distribution in the arm were ascribed to arterial baroreceptor function and not to low pressure baroreceptor activity. The enhancement of venous return during water immersion increased exercise tolerance during heat stress presumably due both to increased stroke volume and decreased venous pooling. The response to sustained handgrip exercise during LBNP and LBPP was not different from control measurements and the effects explained by arterial baroreceptor function. Application of exercise and local hydrostatic stresses in combination with gravitational stresses represent an interesting model for further study of the mechanisms behind the distribution of cardiac output to the peripheral organs.     

Exercise response to simulated weightlessness

Two bed rest analog studies of space flight were performed; one 14 d and the other 28 d in duration. Exercise response was studied in detail during the 28 d study and following both the 14 d and 28 d studies. This paper relates the results of these studies to physiologic changes noted during and following space flight. The most consistent change noted after both bed rest and space flight is an elevated heart rate during exercise. A second consistent finding is a postflight or postbed rest reduction in cardiac stroke volume. Cardiac output changes were variable. The inability to simulate inflight activity levels and personal exercise makes a direct comparison between bed rest and the results from specific space flights difficult.     

Countermeasure of the negative effects of weightlessness on physical systems in long-term space flights

The system of countermcasure of microgravity effects has been developed in Russia that allowed to perform safely long-term space flights. This system that includes different means and methods such as special regimens of physical exercises, axial loading (“Pingiun”) and antigravity suits, low body negative pressure device (LBNP, “Chibis”) and “cuffs” and others has been used with certain variations at certain stages of flight in 27 successfully accomplished space flights that lasted from 60 to 439 days. The pre-, in- and postflight studies performed in 57 crew members of these flights have shown that the system of countermeasure is effective in preventing or diminishing to a great extent almost all the negative effects of weightlessness in flights of a year and more duration and that the intensity and duration of changes recorded in different body systems after flights do not correlate significantly to flight durations, correlating strongly to the volume and intensity of physical exercises used during flight and especially during concluding stage of it.     

Autonomic function testing aboard the ISS using “PNEUMOCARD”

Investigations of blood pressure, heart rate (HR), and heart rate variability (HRV) during long term space flights on board the “ISS” have shown characteristic changes of autonomic cardiovascular control. Therefore, alterations of the autonomic nervous system occurring during spaceflight may be responsible for in- and post-flight disturbances. The device “Pneumocard” was developed to further investigate autonomic cardiovascular and respiratory function aboard the ISS. The hard-software diagnostic complex “Pneumocard” was used during in-flight experiment aboard ISS for autonomic function testing. ECG, photoplethysmography, respiration, transthoracic bioimpedance and seismocardiography were assessed in one male cosmonaut (flight lengths six month). Recordings were made prior to the flight, late during flight, and post-flight during spontaneous respiration and controlled respiration at different rates.HR remained stable during flight. The values were comparable to supine measurements on earth. Respiratory frequency and blood pressure decreased during flight. Post flight HR and BP values increased compared to in-flight data exceeding pre-flight values. Cardiac time intervals did not change dramatically during flight. Pulse wave transit time decreased during flight. The maximum of the first time derivative of the impedance cardiogram, which is highly correlated with stroke volume was not reduced in-flight.Our results demonstrate that autonomic function testing aboard the ISS using “Pneumocard” is feasible and generates data of good quality. Despite the decrease in BP, pulse wave transit time was found reduced in space as shown earlier. However, cardiac output did not decrease profoundly in the investigated cosmonaut.Autonomic testing during space flight detects individual changes in cardiovascular control and may add important information to standard medical control. The recent plans to support a flight to Mars, makes these kinds of observations all the more relevant and compelling.     

Fluid volumes changes induced by spaceflight

The blood volume (BV), plasma volume (PV), and extracellular fluid volume changes produced in crewmembers during spaceflights of 11-84 days were compared to changes after 14 or 28 days of bedrest. Spaceflight and bedrest produce approximately equal BV changes but the recorded PV change after spaceflight was less. However, the diurnal change in PV may explain the smaller decreases recorded after spaceflight. The cardiovascular deconditioning caused by spaceflight and bedrest was compared using the mean heart rate response to lower body negative pressure (LBNP) testing at -50 mmHg pressure. These tests show approximately equal LBNP produced heart rate changes after bedrest and spaceflight. A countermeasure which includes 4 hr of LBNP treatment at -30 mmHg and the ingestion of one l. of saline was studied and found capable of returning the heart rate response and the PV of bedrested subjects to control (prebedrest) levels suggesting that it would be useful to the crewmembers after a spaceflight.     

Recent advances in the physiology of whole body immersion

Recent investigations have furnished a complete analysis of the hemodynamic events accompanying whole-body immersion. About 700 ml of blood are translocated into the intrathoracic circulation, and heart volume increases by 180 +/- 62 ml. These changes are followed by an increase in stroke volume and cardiac output of over 30%. At the same time a reflex reduction of total peripheral resistance and venous tone occurs. Renin and aldosterone activity are reduced while the 17-hydroxycorticosteroid is not affected. Treatment of the subject with DOCA attenuates but does not extinguish the excess sodium excretion of immersion. This finding strengthens the arguments in favor of an unknown factor enhancing sodium excretion. Finally, the relative activation of the three factors that serve volume control, the excretory function of the kidney, capillary filtration pressure, and the thirst mechanism, is discussed.     

Autonomic regulation of circulation and cardiac contractility during a 14-month space flight

The space flight of physician cosmonaut V.V. Polyakov, the longest to date (438 days), has yielded new data about human adaptation to long-term weightlessness. Autonomic regulation of circulation and cardiac contractility were evaluated in three experiments entitled Pulstrans, Night, and Holter. In the Pulstrans experiment electrocardiographic (ECG), ballistocardiographic (BCG), seismocardiographic (SCG), and some other parameters were recorded. In the Night experiment, only the ballistocardiogram was recorded, but a special feature of this experiment is that the BCG records were obtained with a contactless method. This method has several advantages, the most important of which are the possibility of studying slow-wave variations in physiologic parameters (ultradian rhythms) on the basis of recordings made under standard conditions over a prolonged period. The Holter experiment (24-hour electrocardiographic monitoring) used a portable cardiorecorder (Spacelab, USA). The obtained electrocardiographic data were used to analyze heart rate variability. In the first 6 months of the 14-month flight, the dynamics of cardiovascular parameters in V.V. Polyakov was virtually the same as in the other cosmonauts. The data obtained after the first 6 months of Polyakov's sojourn in space are unique and mention should be made of at least three important aspects: (1) activation of a new, additional adaptive mechanism in the 8th-9th months of flight, as is evidenced by alterations in the periodicity and power of superslow wave oscillations (ultradian rhythms) reflecting the activity of the subcortical cardiovascular centers and of the higher levels of autonomic regulation; (2) growth of cardiac contractility accompanied by a decrease in heart rate during the last few months of flight; (3) a considerable increase in the daily average values of absolute power of heart rate's variability MF component, which reflects the activity of the vasomotor center. Specific mechanisms of adaptation to weightless conditions appear to be associated with activation of higher autonomic centers. The hypothesis that central levels of circulation regulation are activated in a long-term space flight was investigated by analyzing of ultradian rhythms in nighttime. The data, received during the flight of V. V. Polyakov, show, that the process of human adaptation to long influence of weightlessness consists of a number of consecutive stages, during which the activation of more and more high levels of control system of physiological functions occurs.     

Correlation of macro and micro cardiovascular function during weightlessness and simulated weightlessness

The investigation of cardiovascular function necessarily involves a consideration of the exchange of substances at the capillary. If cardiovascular function is compromised or in any way altered during exposure to zero gravity in space, then it stands to reason that microvascular function is also modified. We have shown that an increase in cardiac output similar to that reported during simulated weightlessness is associated with a doubling of the number of post-capillary venules and a reduction in the number of arterioles by 35%. If the weightlessness of space travel produces similar changes in cardiopulmonary volume and cardiac output, a reasonable expectation is that astronauts will undergo venous neovascularization. We have developed an animal model in which to correlate microvascular and systemic cardiovascular function. The microcirculatory preparation consists of a lightweight, thermo-neutral chamber implanted around intact skeletal muscle on the back of a rat. Using this technique, the performed microvasculature of the cutaneous maximus muscle may be observed in the conscious, unanesthetized animal. Microcirculatory variables which may be obtained include venular and arteriolar numbers, lengths and diameters, single vessel flow velocities, vasomotion, capillary hematocrit anastomoses and orders of branching. Systemic hemodynamic monitoring of cardiac output by electromagnetic flowmetry, and arterial and venous pressures allows correlation of macro- and microcirculatory changes at the same time, in the same animal. Observed and calculated hemodynamic variables also include pulse pressure, heart rate, stroke volume, total peripheral resistance, aortic compliance, minute work, peak aortic flow velocity and systolic time interval. In this manner, an integrated assessment of total cardiovascular function may be obtained in the same animal without the complicating influence of anesthetics.     

A new application of LBNP to measure orthostatic tolerance before and after 0-g simulation (water immersion)

Lower body negative pressure (LBNP) remains an important device for the generation of orthostatic stress in the space flight environment as well as a tool to measure inflight and postflight changes in orthostatic response.

These applied levels of LBNP have typically not exceeded 50–60 mm Hg negative pressure. Information is incomplete as to the levels of absolute LBNP orthostatic tolerance, and the factors responsible for their variance. A better definition of the tolerance limits for males and females could be expected to aid the evaluation of lower levels of LBNP.

An LBNP device was built to study absolute orthostatic tolerance; additionally, another LBNP device was constructed to permit orthostatic tolerance testing directly after a controlled water immersion period.

Absolute LBNP orthostatic tolerance patterns are analyzed for a group of males and females (series I). A preliminary statement on the variations of LBNP orthostatic tolerance after limited periods of water immersion and bed rest is also provided (series II).     

Effect of a venotonic agent on the main arteries and veins during a 5 day HDT.

Objective: To evaluate the cardiac, arterial and venous effect of a venotonic drug (Cirkan "Ck") administrated orally daily to 6 subjects in HDT position during 5 days. These subjects underwent a second 5d HDT without Ck treatment one month later. Pre and post HDT the subjects were submitted to a stand test. Method: The cardiovascular parameters were measured by echography and Doppler. Results and discussion: The Cirkan treatment contributed to reduce the increase in cerebral resistance, and to maintain the lower limb resistance at a higher level than on controls. It reduces the vein section at the extremities (Jugular, femoral) and in the central vein system connected to the right heart (sub hepatics). On the other hand it increases the portal vein section which means that the blood stagnation at the splanchnic level is increased. Despite these arterial and venous significant modifications the clinical and ECG and Blood pressure response to the Stand test was similar in both groups.     

Cardiovascular deconditioning during weightlessness simulation and the use of lower body negative pressure as a countermeasure to orthostatic intolerance

The cardiovascular function is one of the main disturbed by weightlessness: it is particularly affected by the astronaut's return to Earth, where symptoms linked to the cardiovascular deconditioning syndrom appear in the following forms: (1) orthostatic intolerance with its risk of syncope: (2) higher submaximal oxygen consumption for an equivalent work load. Lower Body Negative Pressure (LBNP) is intended to stimulate the venous system of the lower limbs; however, the specific effects of periodical LBNP sessions on the orthostatic intolerance have never been studied. With this objective in mind, 5 volunteers took part in two recent antiorthostatic bedrest experiments for 30 days. In the first experiment 3 subjects were submitted to several sessions of LBNP experiment per day and 2 others were controls; in the second experiment the LBNP group of the 1st one became controls and vice-versa. Two orthostatic investigations were performed: (1) 5 days before the bedrest; (2) at the end of the 30 day bedrest period. The results showed: (1) when the subjects were control, a high orthostatic intolerance post bedrest with 3 syncopes and one presyncopal state during the first minutes of the tilt test; (2) when the subjects were submitted to LBNP sessions, no orthostatic intolerance.     

Right ventricular tissue Doppler assessment in space during circulating volume modification using the Braslet device

Introduction: This joint US–Russian work aims to establish a methodology for assessing cardiac function in microgravity in association with manipulation of central circulating volume. Russian Braslet-M (Braslet) occlusion cuffs were used to temporarily increase the volume of blood in the lower extremities, effectively reducing the volume in central circulation. The methodology was tested at the International Space Station (ISS) to assess the volume status of crewmembers by evaluating the responses to application and release of the cuffs, as well as to modified Valsalva and Mueller maneuvers. This case study examines the use of tissue Doppler (TD) of the right ventricular (RV) free wall. Results: Baseline TD of the RV free wall without Braslet showed early diastolic E′ (16 cm/s), late diastolic A′ (14 cm/s), and systolic S′ (12 cm/s) velocities comparable with those in normal subjects on Earth. Braslet application caused 50% decrease of E′ (8 cm/s), 45% increase of A′, and no change to S′. Approximately 8 beats after the Braslet release, TD showed E′ of 8 cm/s, A′ of 12 cm/s, and S′ of 13 cm/s. At this point after release, E′ did not recover to baseline values while l A′ and S′ did recover. The pre-systolic cross-sectional area of the internal jugular vein without Braslet was 1.07 cm², and 1.13 cm² 10 min after the Braslet was applied. The respective cross-sectional areas of the femoral vein were 0.50 and 0.54 cm². The RV myocardial performance Tei index was calculated by dividing the sum of the isovolumic contraction time and isovolumic relaxation time by the ejection time ((IVCT+IVRT)/ET); baseline and Braslet-on values for Tei index were 0.25 and 0.22, respectively. Braslet Tei indices are within normal ranges found in healthy terrestrial subjects and temporarily become greater than 0.4 during the dynamic Braslet release portion of the study. Conclusions: TD modality was successfully implemented in space flight for the first time. TD of RV revealed that the Braslet influenced cardiac preload and that fluid was sequestered in the lower extremity interstitial and vascular space after only 10 min of application. This report demonstrates that Braslet application has an effect on RV physiology in long-duration space flight based on TD, and that this effect is in part due to venous hemodynamics.     

System identification of dynamic closed-loop control of total peripheral resistance by arterial and cardiopulmonary baroreceptors.

Prolonged exposure to microgravity in space flight missions (days) impairs the mechanisms responsible for defense of arterial blood pressure (ABP) and cardiac output (CO) against orthostatic stress in the post-flight period. The mechanisms responsible for the observed orthostatic intolerance are not yet completely understood. Additionally, effective counter measures to attenuate this pathophysiological response are not available. The aim of this study was to investigate the ability of our proposed system identification method to predict closed-loop dynamic changes in TPR induced by changes in mean arterial pressure (MAP) and right atrial pressure (RAP). For this purpose we designed and employed a novel experimental animal model for the examination of arterial and cardiopulmonary baroreceptors in the dynamic closed-loop control of total peripheral resistance (TPR), and applied system identification to the analysis of beat-to-beat fluctuations in the measured signals. Grant numbers: NAG5-4989.