Effect of Coenzyme Q10 Supplementation on Sarcopenia, Frailty, and Falls: A Scoping Review

Abstract

Coenzyme Q10 (CoQ10) is well-known for its antioxidant effects and has been highlighted in research related to aging and many age-related conditions. However, there is limited research on the benefit of CoQ10 supplementation in conditions impacting the physical robustness of older adults, such as sarcopenia, frailty, falls and osteoporosis. This scoping review identified and summarized 4 studies that assessed the effects of exogenous CoQ10 on outcomes relating to sarcopenia, frailty, and falls. Results of the studies showed statistically significant improvements in a variety of physical robustness related outcomes, however several limitations of these studies prevent conclusive recommendations from being drawn regarding the benefit of CoQ10 supplementation in these conditions. A well-designed randomized control trial assessing the benefit of CoQ10 supplementation on clinically relevant outcomes related to sarcopenia, frailty, and falls may be warranted.

Introduction

With advances in medical research, pharmacotherapy and a greater focus on disease prevention, the population is aging and the global life expectancy is now 73.4 years (1). Alongside the growing population of older adults, there is also an increase in the prevalence of a number of chronic medical conditions more prominent in this age group including sarcopenia, frailty and osteoporosis (2). These conditions play a major role in falls-related injuries (e.g. hip fracture), mortality and overall quality of life for older adults (2). Thus, much research has focused on the investigation of safe and effective therapeutic alternatives to prevent and/or treat these conditions and their associated complications.

Due to its antioxidant capabilities and involvement in cellular bioenergetics, Coenzyme Q10 (CoQ10) has been a focus of medical research in recent decades. CoQ10 is synthesized endogenously as well as obtained through diet. It partakes in many antioxidant and anti-inflammatory activities, including the prevention of free radical formation; protection of cell membranes, lipoproteins, and DNA; and may also influence gene expression through regulation of NF-kB pathway (3, 4, 5, 6). CoQ10 deficiency has been linked to many chronic inflammatory conditions and as such, CoQ10 research has predominantly focused on supplementation in patients living with diabetes, cardiovascular disease, migraine headache, or management of adverse events involving medications that disrupt endogenous CoQ10 production (e.g. HMG CoA reductase inhibitors) (6, 7, 8, 9).

Preclinical data has suggested a potential role of CoQ10 in a number of conditions predominantly affecting older adults, including sarcopenia, frailty, falls and osteoporosis. An association has been demonstrated between plasma levels of CoQ10 and outcomes related to grip strength, muscle composition and muscle mass (10, 11). Given that these measures are part of the diagnostic criteria for sarcopenia, it is plausible that CoQ10 may play an important role in the pathogenesis of the disease (12). CoQ10 supplementation has also been shown to enhance peak power, albeit in younger athletes (13). It is unclear if the same benefits are seen in older adults or those with sarcopenia. Beyond sarcopenia, muscle strength and physical fitness are also important indicators of physical frailty (14). CoQ10 is postulated to have a positive effect on physical frailty-related outcomes, such as physical robustness, however, these effects are extrapolated from the impact of CoQ10 on physical performance and recovery time in younger athletes (15). Little is known about the impacts of CoQ10 on physical or clinical frailty in the older population. In addition to strength related outcomes, CoQ10 has been shown to have potential benefits in osteoporosis in preclinical studies. In animal studies, CoQ10 supplementation has been shown to prevent bone loss and decrease bone resorption in rats (16). There is, however, limited data on the effects of CoQ10 supplementation for osteoporosis in humans.

Although CoQ10 is associated with a potential benefit in conditions that typically affect the physical robustness of older populations, most studies have been done without exogenous supplementation, in younger populations or in non-human subjects. Thus, this scoping review attempts to summarize what is known on the benefits of CoQ10 supplementation on physical robustness of older adults, including falls, frailty, osteoporosis and sarcopenia.

Methods

A scoping review was conducted following the 2018 Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist (17). This framework allowed for thorough analysis of study designs and characteristics as well as research gaps in order to better understand the types of available evidence on this topic (18).

Search Strategy

The search strategy was designed by investigators and reviewed by a medical librarian. Two databases, Medline and Embase, were searched from inception to February 22, 2023. Search terms related to coenzyme Q10, older adults, physical robustness, frailty, falls, sarcopenia and osteoporosis were used. A manual review of references lists of retrieved studies and review articles from the original search, as well as the Natural Medicines database, was also performed (19). An example of our search string is available in the Appendix.

Selection Criteria

Studies were eligible for inclusion if the population consisted of older adults (mean age 50 years or greater), the intervention was exogenous CoQ10 supplementation in the form of a single or multi-component supplement, and the outcomes focused on measures of physical robustness or medical conditions directly influenced by physical robustness including falls, frailty, osteoporosis and sarcopenia. Publications on the use of CoQ10 in younger adults (mean age under 50 years), other medical conditions (i.e. migraines, cardiovascular disease, drug-induced diseases, CoQ10 deficiency syndromes) or dietary CoQ10 interventions were excluded. Additionally, non-human studies, those published in a non-English language and those without an available full text were excluded.

Data Extraction

All retrieved citations were imported into Covidence (www.covidence.org). Titles and abstracts were screened by two independent reviewers (JB, SS). Potentially eligible studies were subjected to a full text review by both reviewers to confirm the inclusion and exclusion criteria were met. Disagreements were resolved by consensus. Data on author, year of publication, study origin, study design, demographics, sample size, duration, intervention, relevant outcomes, results, and any limitations were collected in duplicate.

Quality Assessment

Quality of included studies was assessed using the Joanna Briggs Institute (JBI) tools. Randomized controlled trials, including cross-over studies, were assessed using the JBI Critical Appraisal Tool for Assessment of Risk of Bias for Randomized Controlled Trials (20). Prospective observational studies were assessed using the JBI Checklist for Cohort Studies (21).

Results

Our search strategy yielded 2506 articles. After duplicates were removed, the titles and abstracts of 2066 articles were screened. Seventeen studies were identified for full text review, of which 4 studies were ultimately included (Figure 1).

Figure 1.

Study selection diagram

Study Characteristics

Two of the included studies were randomized control trials, one was a double blinded placebo controlled cross-over study, and one was an observational study (Table 1). The sample sizes ranged from 8 to 108 participants with mean ages between 60–70 years. CoQ10 supplementation ranged from 100 to 300mg daily for 1.5 to 4 months and was administered with other vitamins or supplements in all four studies. Outcomes were reported that were relevant to sarcopenia (two studies), frailty (three studies) and falls (one study) (Table 2). No studies reported on osteoporosis-related outcomes. Two studies reported on a separate study arm not relevant to this scoping review; one study assessed CoQ10 in both younger and older adults and one study assessed CoQ10 and dry chemical heat wraps in older adults (22, 23). Only the results of the CoQ10 interventions in older adults are reported herein.

Table 1.

Study Characteristics

Article	Design	Sample	Intervention	Comparator	Outcome	Measures	Key results	JBI Quality Assessment
Negro et al., 2019 (24)	Randomized control trial	n=38 participants age 65 or older (mean age 70 years)	Muscle Restore Complex® plus Essential amino acid-based multi-ingredient supplementa containing 50mg of CoQ10 taken twice daily. Treatment duration: 12 weeks	Baseline and Placebo	Muscle mass, muscle strength, muscle power	ALM, ALM index, PP, MVC	Statistically significant increase in ALM, ALM index, PP, MVC	10/13c
Petrofsky et al. 2016 (23)	Randomized control trial	n=80 participants age 55 to 64 with mobility impairment (mean age 60 years) Subgroup of study	300mg of CoQ10 taken daily. Taken with 4000 units vitamin D, 1000 units vitamin E, 600mg Calcium, and 1 multivitamin (Centrum Silver). Treatment duration: 16 weeks	Control	Mobility and balance	MVC%, Gait velocity, Gait symmetry, TUG, postural sway	Statistically significant difference in measures of mobility and balance	9/13c
Ganguly, 2019 (25)	Prospective observational study	n= 108 participants with osteoarthritis age 40 to 75 years (mean age 61)	Jumpstart Nutritional Supplement®b containing 100mg of CoQ10 taken daily. Treatment duration: 8 weeks	Control	Ability to complete ADLs	KPS. KOOS (ADL)	Statistically significant increase in ability to carry out ADLs	2/8d
Laaksonen et al., 1995 (22)	Double blinded placebo controlled crossover study	n=8 athletic participants age 60 to 74 years (mean age 64 years) Subgroup of study	Kino-Q-10 supplement containing 120mg of CoQ10 taken daily. Taken with 500mg of fish oil. Treatment duration: 6 weeks	Placebo	Aerobic capacity	VO2 Max, Time to exhaustion	No significant improvement in max or time to exhaustion	9/12c

ALM= Appendicular Lean Mass, ALM index= Appendicular Lean Mass divided by height squared, KOOS (ADL) = Knee osteoarthritis outcome scale (activities of daily living subsection), KPS = Karnofsky Performance Scale, MVC= maximum voluntary contraction, PP= peak power, TUG= Time up and go, VO₂ max = maximal oxygen uptake. ^a Supplement also contained 1400mg L-leucine, 600mg L-Phenylalanine, 700mg L-Lysine, 670mg L-Isoleucine, 700mg L-Valine, 450mg L-Threonine, 290mg L-Methionine, 190mg L-Tryptophan, 1500mg creatine, 1000 IU vitamin D, 300mg ALA, 50mg resveratrol; ^b Supplement also contained 737 mg of minerals composed of calcium, phosphorus, and iron in the ratio 5:4:0.21, Vitamin C 25mg, Folic acid 100mcg, Vitamin K2 20mcg, Vitamin D2 8mcg, 275 mg of other phytonutrients such as boswellic acids and curcumin in the ratio 8:3 mixed with protein powders of soy and whey in the ratio 3:7; ^c Joanna Briggs Institute Randomized Controlled Trials Critical Appraisal Tool, 1 item was not applicable in 1 study (Laaksonen); ^d Joanna Briggs Institute Cohort Study Critical Appraisal Tool, 3 items were not applicable

Table 2.

Extracted Study Outcomes Related to Conditions Affecting Physical Robustness in Older Adults

Geriatric Conditions	Measures Reported in Studies
Sarcopenia	ALM, ALM index (24) Gait velocity (23) TUG test (22)
Frailty	KPS (25) KOOS-ADL (25) Gait Velocity (23) ALM index (24)
Falls	TUG test (23) Postural Sway (23) Gait Velocity (23) Gait Symmetry (23)
Other reported measures of physical robustness	MVC (24) PP (24) MVC% (23) Time to exhaustion (22) VO2 max (22)

ALM= Appendicular Lean Mass, ALM index= Appendicular Lean Mass divided by height squared, KOOS (ADL) = Knee osteoarthritis outcome scale (activities of daily living subsection), KPS = Karnofsky Performance Scale, MVC= maximum voluntary contraction, PP= peak power, TUG= Time up and go, VO₂ max = maximal oxygen uptake.

Appendicular Lean Mass (ALM)

Appendicular Lean Mass (ALM) and ALM index are measures relevant to sarcopenia and physical frailty. Negro et al. assessed the impact of CoQ10 on ALM and ALM index (24). ALM was taken as the sum of the fat-free soft tissue mass of arms plus legs and ALM index was calculated by dividing the ALM by the height in meters squared. At baseline, the CoQ10 group had a mean ALM and ALM index of 20.26 +/− 4.80 kg and 7.82 +/− 1.09 kg/m² respectively. After 12 weeks, there was a statistically significant increase from baseline in both mean ALM (0.34 kg) and mean ALM index (0.12 kg/m²) (p<0.001). There was no statistically significant change in the placebo group.

Timed Up and Go (TUG) test

The timed up and go (TUG) test is a measure that can be used in the assessment of sarcopenia and falls. Petrofsky et al. assessed the impact of CoQ10 on the TUG test (23). The TUG test was performed by having participants sit in a chair and on visual command stand up and walk 3 meters. After 16 weeks of treatment, participants randomized to the CoQ10 arm of the study were found to have a statistically significant decrease in their TUG test time compared to baseline (13.9 +/− 1.9 seconds vs. 15.2 +/− 2.9 seconds, p<0.05) while no significant difference was seen in the control arm.

Gait Velocity, Gait Symmetry and Postural Sway

Gait velocity can be used for the assessment of sarcopenia, falls and physical frailty while gait symmetry and postural sway can be clinical markers used in falls risk assessment. Petrofsky et al. looked at the impact of CoQ10 on gait velcocity, gait symmetry and postural sway (23). Gait velocity was measured as participants walked at a self-paced speed. At baseline, gait velocity for the CoQ10 group was 88.4 +/− 12.3 cm/s, which increased at study completion to a mean of gait velocity of 99.1+/− 15.1 cm/s (p<0.05). Gait symmetry was expressed by the coefficient of variance of the weight shift with walking. There was a statistically significant decrease from baseline in the coefficient of variance in gait symmetry in the CoQ10 group (15.8 +/− 3.6 vs. 14.8 +/− 4.2). Postural sway was measured by having participants perform 8 balance tests on a force platform. There was a statistically significant decrease in sway with CoQ10 in 6 of the most difficult balance tests (p<0.05). There was no statistically significant difference in gait velocity, gait symmetry or postural sway in the control arm of the study.

Karnofsky Performance Scale and Knee Osteoarthritis Outcome Scale Activities of Daily Living

Ganguly assessed the impact of CoQ10 on the Karnofsky Performance Scale (KPS) and the activities of daily living subsection of the Knee Osteoarthritis Outcome Scale (KOOS-ADL), two measures applicable to the assessment of clinical frailty (25). The KPS ranges from 0 to 100 with a higher score indicating a better condition to carry out ADLs. At baseline, the approximate KPS for the CoQ10 (females: 40, males: 45) and control groups (female: 40, males: 55) were not statistically different. After eight weeks of supplementation, the approximate scores were significantly higher in the CoQ10 group (females: 70, males: 80) compared to the control group (females: 35, males: 40) (p<0.05). The KOOS-ADL is one of five sections of the KOOS and is designed to assess patientrelevant outcomes following knee injury. The KOOS-ADL is composed of 17 questions and is translated to a score from 0 to 100 with 0 indicating extreme functional problems relating to the knee and 100 indicating no functional issues of the knee (26). The approximate baseline KOOS-ADL scores were similar for participants in the CoQ10 group (females: 20, males: 30) and the control group (females: 20, males: 35). After 8 weeks of supplement use there was a statistically significant increase in KOOS-ADL scores in the CoQ10 group (females: 90, males: 80) compared to the control (females: 15, males: 25). The decrease in scores in the control group for both the KPS and KOOS-ADL questionnaire were not statistically significant.

Peak Power, Maximal Voluntary Contraction, Time to Exhaustion and VO₂ Max

Peak power (PP), maximal voluntary contraction (MVC) and maximal voluntary contraction percentage (MVC%) are measures that can describe muscular strength while time to exhaustion and VO₂ max can describe physical performance. Negro et al. assessed the impact of CoQ10 compared to placebo on PP and MVC of the bicep (24). In the CoQ10 arm of the study, the mean baseline PP and MVC were 29.72 +/− 17.45 watts and 9.06 +/− 3.46 kg, respectively. These values increased by a mean of 4.82 watts and 0.52 kg, respectively at study completion (p<0.001). Conversely, in the placebo arm baseline PP and MVC were 41.04 +/− 26.40 watts and 9.97 +/− 4.11 kg, respectively, both of which decreased at study completion by a mean of 5.04 watts (p>0.05) and 0.86 kg (p<0.001), respectively. Petrofsky et al. analyzed the impact of CoQ10 on MVC% of the lower limb while participants walked on a treadmill. There was a statistically significant improvement in MVC% after 16 weeks of CoQ10 supplementation wherein the MVC% increased from 20.2 +/− 7.8 at baseline to 29.3 +/− 9.2 (p<0.05) at study completion while no significant change was seen in the control arm (23). Laaksonen et al. assessed the effect of CoQ10 on time to exhaustion and VO₂ max on an ergometer (22). There was no statistically significant difference in VO₂ max between the CoQ10 and placebo arms (33.7 ml/min/kg and 37.2 ml/min/kg), while time to exhaustion was significantly shorter with CoQ10 (77.2 minutes) compared to placebo (82.9 minutes) (p=0.003).

Discussion

This scoping review included 4 studies that assessed the effectiveness of CoQ10 supplementation on outcomes relating to sarcopenia, frailty, and falls in older adults. Overall, the included studies found statistically significant improvements in several measures; however, the results require cautious interpretation due to a number of limitations in study design, patient population, and clinical measures.

Sarcopenia

Sarcopenia can be diagnosed through measures including ALM, TUG test, gait velocity, and grip strength (12). The European Working Group for Sarcopenia in Older People (EWGSOP2) define sarcopenia as an ALM less than 20kg for men and 15 kg for women and an ALM index under 5.5 kg/m² for women or 7.0 kg/m² for men (27). Similarly, the International Working Group for Sarcopenia (IWG) uses an ALM index ≤ 5.67 kg/m² in women and ≤ 7.23 kg/m² in men for diagnosis of sarcopenia (12). While participants randomized to CoQ10 in the study by Negro et al did have a statistically significant increase in ALM and ALM index, they did not meet either EWGSOP2 or IWG criteria for sarcopenia at baseline (24). Similarly, the EWGSOP2 uses a TUG test time of >20s in their definition of sarcopenia and while participants in the study by Petrofsky et al had a statistically significant decrease in their TUG test time, the mean TUG test at baseline was <20 seconds (23, 27). As such, the potential benefits seen in these studies may not be applicable to individuals who are already sarcopenic.

The value of ALM as a predictor of sarcopenia-related outcomes has recently been questioned. The Sarcopenia Definition and Outcomes Consortium found that low ALM was not associated with incident adverse health-related outcomes in community-dwelling older adults (28). However, they did find that low gait speed was a predictor of falls, self-reported mobility limitation, hip fractures, and mortality (28). Both the EWGSOP2 and IWG do use gait speed in their definitions of sarcopenia. The EWGSOP2 uses a gait speed of <0.8 m/s while the IWG uses <1.0 m/s (12, 27). At baseline, participants in the study by Petrofsky et al. had a mean gait speed of 0.88 m/s, meeting the IWG criteria for sarcopenia (23). However, at study completion mean gait velocity in the CoQ10 arm did not exceed the IWG threshold of 1m/s. Thus, the benefits seen in this study cannot be assumed to have made a clinically meaningful impact on sarcopenia.

Grip strength is also a commonly used measure in the assessment of sarcopenia (12). Grip strength was not performed in any of the studies, instead, muscle strength was measured using peak power and maximal voluntary contraction. It is currently unknown if these measures correlate with clinically meaningful outcomes of sarcopenia.

Frailty

Physical frailty can be identified using measures including unintentional weight loss, self-reported exhaustion, weakness, slow walking speed, and low physical activity (14). Outcomes related to physical frailty obtained from studies in this scoping review include gait speed, ALM index and time to exhaustion. Similarly to sarcopenia, the cut-offs for risk of frailty-related adverse outcomes associated with gait speed are between 0.8 m/s to 1m/s (29). Because baseline gait speed in the study by Petrofsky et al exceeded 0.8m/s and the post-intervention gait speed did not exceed 1m/s, the benefits of CoQ10 on gait velocity found within this study may not be applicable to individuals living with physical frailty (23). The usefulness of the ALM index to identify frailty is also controversial. One study found that the ALM index had no association with frailty or physical limitations. However, they did find that an ALM to BMI ratio may be more suitable to detect patients at risk for negative outcomes associated with frailty (30). The ALM to BMI ratio was not assessed in any of the included studies. The measures of self-reported exhaustion using time to exhaustion and VO₂ max reported by Laaksonen et al may be considered relevant to physical frailty (22). However, the population in this study were older athletes and may not be reflective of the general population of older adults or those living with frailty.

Clinical frailty describes the degree to which frailty impacts the functional ability of older adults (31). The Clinic Frailty Scale (CFS), evolved from the Canadian Study of Health and Aging, is a common tool used to assess frailty via questions on mobility, physical activity and independence with ADLs and instrumental ADLs (iADLs) (31). Ganguly assessed the impact of CoQ10 on functional independence with the KPS and KOOS-ADL tools (25). While the KPS has similar components to that of the CFS, it is most typically used to assess functional impairment in cancer patients while the KOOS-ADL focused on knee impairment, although it did include questions relating to mobility, functional independence and quality of life (26, 32). Both questionnaires saw a significant improvement in scores after the intervention, however this was an observational study and did not disclose how participants were allocated to receive treatment or whether participants were receiving additional treatment of their osteoarthritis.

Falls

Gait and balance can both be predictors of falls in the elderly. In a 2018 cross-sectional study in elderly participants, researchers found that a gait speed of less than 1.0 m/s was associated with an increased risk of falling, although it was noted that gait speed alone may not be sufficient to identify high risk individual (33). In the study by Petrofsky et al. the baseline gait speed was below 1.0m/s, indicative of a potential falls risk (23). Despite a statistically increase in gait speed with CoQ10, the gait speed remained below 1.0m/s at study completion suggesting the participants continued to be at increased risk of falls. TUG test time of over 12 seconds are also associated with an increased risk of falls (34). In the same study, at baseline and after the intervention, the CoQ10 arm had a TUG test time over 12 seconds, aligning with a higher risk of falls and lack of significant impact of the intervention on risk of falls (23). Postural sway was measured using the coefficient of variance (CV) of the polar vector of weight displacement using a force platform (23). Although there is some evidence to suggest force platform measurements may be a predictor for falls, the displacement of center of pressure (CoP) appears to be a more standardized measure (35). It is unclear if the measurement used in the study holds the same validity of CoP displacement.

Impact of Other Vitamins and Supplements

All four studies included other vitamins or supplements as part of the intervention, therefore, we cannot isolate CoQ10 for being solely responsible for any of the outcomes. Three of the four studies included vitamin D, two included calcium, and one included omega-3, all of which have been associated with improvements in frailty, sarcopenia, or falls (36, 37). In a 2021 meta-analysis, researchers found that omega-3 supplementation may have a positive effect on overall muscle mass and strength (36). Additionally, a 2017 meta-analysis found that vitamin D plus calcium supplementation has a significant effect on the reduction in the risk of falls (36). Other supplements used in the studies like creatine and whey protein may also have a positive effect on muscle strength and lean mass (38). As such, the potential benefits seen within the included studies may be a result of the multi-component intervention used in each of the studies.

Limitations

This review is not without its limitations. By adhering to our inclusion criteria, we excluded many studies that focused on other medical conditions that typically affect the older population and thus may have lead to a limited number of relevant studies. Some articles were not available in English full text and were not included in this review. The heterogeneity of reported outcomes precluded the ability to meta-analyze our findings.

The studies included in this review also had several limitations. Firstly, the studies all had a small sample size and a short duration (between 1.5 and 4 months). Secondly, the studies generally included a healthy population of older adults, so the findings may not apply to those who are sarcopenic or frail at baseline. Additionally, some of the measures differed from those typically employed for the evaluation of outcomes like sarcopenia, frailty, or falls. For example, hand grip strength is one of the most common measures of sarcopenia and this was not assessed in any of the studies. Lastly, the description of some measures were vague, making it difficult to interpret the applicability.

Recommendations

The current clinical evidence does not suggest a significant benefit of the use of CoQ10 for the treatment or prevention of sarcopenia, frailty, falls, or osteoporosis and therefore, cannot be recommended for these conditions at present. Based on the preclinical data from other animal studies, those in younger populations, and studies assessing CoQ10 levels, a well-designed randomized control trial may be warranted to properly assess the benefit of exogenous CoQ10 supplementation in older adults with or at risk for conditions impacting their physical robustness. Should such a study be done, the intervention should include only CoQ10 with no additional vitamins or supplements and should be done in a population that has established sarcopenia, frailty, or falls risk and use clinically relevant outcomes such as grip strength for sarcopenia or CFS for clinical frailty.

Conclusion

There is limited research assessing the benefit of CoQ10 supplementation in conditions that affect the physical robustness of older adults such as sarcopenia, frailty, falls, and osteoporosis. The studies included in this scoping review revealed that CoQ10 supplementation, along with other vitamins and supplements, may have a positive effect on surrogate outcomes related to physical robustness. However, the limitations of the available studies make it difficult to draw conclusions on the effectiveness of CoQ10. Future well-designed randomized control trials with CoQ10 supplementation in an older population are recommended prior to therapeutic use of CoQ10 for these outcomes.

Funding

The authors did not receive support from any organization for this work.

Contributions

JB and AM designed the study. JB and SS conducted the literature review. JB, SS and AM wrote the manuscript.

Declaration of interest statement

The authors report there are no competing interests to declare.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s12603-023-1943-8.

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