Lieber Jaaos 2002

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Vol 10, No 1, Jan uary/February 2002 67

Delayed-onset muscle soreness(DOMS), or what is commonly

described as postexercise musclesoreness, is the sensation of muscu-lar discomfort and pain duringactive contractions that occurs in adelayed fashion after strenuousexercise. Usually, the initial symp-toms are most evident at the mus-cle tendon junction and thereafterspread throughout the entire mus-cle. Skeletal muscle soreness andinjury are associated with intenseexercise. The soreness and accom-

panying muscle damage are evenmore pronounced if the exerciseperformed is new to the individual.Thus, even individuals who are inexcellent athletic condition may ex-perience muscle soreness and dam-age when performing exercise towhich they are unaccustomed. Therelationship between the develop-ment of DOMS and the loss of mus-cle strength has yet to be explicitlyproven.

Symptoms

Sore muscles after exercise are usu-ally described as stiff, tender, oraching. The stiffness associated withDOMS is not a function of antago-nistic muscular action but is proba-bly caused by edema occurring inthe perimuscular connective tissue.1

The symptoms of DOMS developduring the first 24 to 48 hours, peakbetween 24 and 72 hours, and disap-pear within 5 to 7 days,2,3 usuallywithout intervention. Regardless of

the exact location of the palpableregion of soreness, passive stretch-ing and renewed activity aggravatethe pain. Some controversy existsregarding the relationship betweenmaximum voluntary force andsymptoms of soreness. Ebbelingand Clarkson3 suggested that thereis very little or no relationship be-tween the development of sorenessand a decrease in muscle strength.Newham et al4 demonstrated return

of maximum quadriceps strength topre-exercise levels within 24 hoursafter step exercise, while others havereported that a period of >2 weeks isnecessary to recover maximum iso-

metric strength. In addition to ten-derness with palpation, the examineralso will find prolonged strengthloss, a reduced range of motion, andelevated levels of serum creatinekinase (CK).

Many studies have reported thateccentric exercise results in a signifi-cant increase in CK levels 24 to 48hours after the exercise session5 thatmay peak between 3 to 6 days, de-pending on the precise nature of the

exercise (Fig. 1, open circles). CK isan intramuscular enzyme responsi-ble for maintaining adequate adeno-sine triphosphate levels duringmuscle contraction. Its appearancein the serum is interpreted as indi-cating an increased permeability orbreakdown of the membrane sur-

Dr. Lieber is Professor of Orthopaedics andBioengineering, Veterans Affairs MedicalCenter, and Department of Orthopaedics andBioengineering, University of California, SanDiego, Calif. Dr. Fridn is Professor of HandSurgery, Department of Hand Surgery,Gteborg University, Gteborg, Sweden.

Reprint requests: Dr. Lieber, University ofCalifornia San Diego School of Medicine, 3350La Jolla Village Drive, San Diego, CA 92161.

Copyright 2002 by the American Academy ofOrthopaedic Surgeons.

Abstract

Muscle pain after unaccustomed exercise is believed to result from repeti-tive active lengthening of skeletal muscle. This eccentric exercise initi-ates a sequence of events that includes muscle cytoskeletal breakdown,inflammation, and remodeling such that subsequent exercise sessions resultin less injury and soreness. Recent studies of eccentric exercise using well-

defined animal models have identified the mechanical and cellular eventsassociated with the injury-repair process. In addition, neurophysiologicstudies have elucidated mechanisms of pain that operate in skeletal muscle.Taken together, these studies improve our understanding of the muscleinjury process and will lead to rational therapeutic interventions to facili-tate recovery.

J Am Acad Orthop Surg 2002;10:67-73

Morphologic and Mechanical Basis o f

Delayed-Onset Muscle Soreness

Richa rd L. Lieber, PhD, and Jan Fridn, MD, PhD


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rounding the muscle cell. IncreasedCK levels resolve in 7 to 14 days. In

a similar delayed fashion, musclepain accompanying eccentric exer-cise peaks 24 to 48 hours after theexercise session but resolves morerapidly compared with CK levels.Interestingly, peak CK levels are notstrongly correlated with either thetiming of increased muscle pain orthe magnitude of tissue injury.

Another widely agreed-on find-ing is that training prevents or atleast attenuates the magnitude of

muscle injury that occurs aftereccentric exercise (Fig. 1, solid cir-cles). This training effect is pro-duced only after eccentric trainingof the specific muscle group beingtested. In other words, there is avery high degree of specificityregarding the protective effect ofexercise. General increased aerobicfitness neither prevents nor attenu-ates eccentric contraction-inducedmuscle injury.

Skele tal Muscle Injury

Injury to muscle fibers can occur asa result of direct trauma, disease, ap-plication of myotoxic agents (such aslocal anesthetics), inflammatoryprocesses, or intense exercise. Theassociation between the type of in-jury and the nature of the pain thataccompanies it has been studiedusing a number of experimentalmodels. Results from these studiesclarify the various mechanisms ofmuscle fiber injury and factors that

influence the type and duration ofpain associated with it. The modelmost commonly used to studyDOMS is the eccentric contractionmodel.

Muscle Injury Resulting From

Eccentric Contractions

Among the variety of types ofmuscle action are the eccentric, con-centric, and isometric. During aneccentric action, an activated muscle

is forced to elongate while produc-ing tension. Its counterpart, concen-tric action, produces tension duringmuscle shortening. The intermedi-ate, isometric contraction producestension while the muscle remains

essentially at a constant length. Allthree actions are common compo-nents of daily movement. The ten-sion generated during eccentricaction is higher than that for eitherof the other actions. Asmussen6 es-tablished that DOMS was primarilyassociated with the eccentric com-ponent of exercise. A muscle injurymodel utilizing eccentric contrac-tion, in which the muscle is activelygenerating force during the length-

ening maneuver, has been imple-mented in animals as well as hu-mans.

Based on experimental studies ofskeletal muscles directly subjectedto eccentric exercise, investigatorsbelieve that the very early eventscausing muscle injury are mechani-cal in nature.7,8 For example, duringcyclic eccentric exercise of the rabbittibialis anterior, significant mechan-ical changes were observed in the

first 5 to 7 minutes of exercise. Afterthis period, histologic examinationrevealed that a small fraction ofmuscle fibers appeared to be larger,more rounded, and more lightlystained compared with surroundingnormal muscle fibers. Interestingly,recent immunohistochemical stud-ies have revealed structural disrup-tion of the cytoskeleton within thefibers at these very earlier time peri-ods9 that may provide further in-

sights into the damage mechanism.Such pathologic changes also can beseen following either sprint or dis-tance running in humans and afterresistance training.10,11

Fiber Type -Spec ific Dam age

Both animal and human studieshave provided evidence for selec-tive damage of fast fiber types aftereccentric exercise.12,13 In humanstudies, this damage was confined

D elayed -O nset M uscle Soreness

Journal of the American Academy of Orthopaedic Surgeons68

Hours Days

Trained

Untrained

3300

2000

1000

500

200

100

60

SerumCK

(IU/ml,Lo

gScale)

0 3.75 1 2 3 5 7 9 11

Figure 1 Time course of serum CK levels after a session of eccentric exercise in untrainedand trained young men. Note that the delayed and prolonged increase in CK levels inuntrained individuals is attenuated after training. (Reproduced with permission fromLieber RL [ed]: Skeletal Muscle Structure and Function: Implications for Rehabilitation andSports Medicine. Baltimore, Md: Williams & Wilkins, 1992.)


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to the type 2 muscle fibers in gener-al (Table 1), but in animal studies,damage has been further localizedto the type FG (often equated totype 2B) fast fiber subtype. In onestudy,12 231 enlarged rabbit tib-

ialis anterior fibers were observedfrom six different muscles; all wereof the FG fiber type. Their averagesize was about four times the nor-mal muscle fiber area. For somefibers observed in serial section, thearea and shape of the fiber changeddramatically from one section to thenext12 (Fig. 2). Because FG fibersare the most highly fatigable musclefibers, it has been speculated thatthe high degree of fatigability of

these fibers may predispose them toinjury, but this has not been sup-ported in detailed animal studies.14

At the ultrastructural level, themost commonly reported morpho-logic abnormality is the loss of theregular orientation of Z bands withthe fibers. The most subtle form ofinjury is the slight wavy appear-ance of the Z band, while moresevere injury is manifest by com-plete Z band or A band disruption

(Fig. 3). Despite the numerous re-ports of this phenomenon, a mecha-nistic explanation for selective Zband damage is not available.

Inflammation After

Musc le Injury

Direct evidence of inflammatorycells within skeletal muscle after ec-centric exercise has been reported inboth animals and humans.5,15 The

early mechanical events are fol-lowed by infiltration of circulatingmonocytes that become macro-phages after entering the tissue (Fig.4). In a study of the rabbit tibialisanterior,12 the time course of torquegeneration in rabbit dorsiflexorswas measured after a single eccen-tric exercise session; there was a mea-surable progressive decline in forcethat was delayed and occurred overa 2- to 3-day period. The mecha-

nism for the progressive decline inforce was hypothesized by the au-thors to be the infiltration of inflam-matory cells and associated proteo-lytic degradation of muscle tissue.In this model, the progressive forcedecline was about the same order ofmagnitude as the force decline thatoccurred as a result of the mechani-cal injury itself. Cellular infiltrationwas uniquely associated with theeccentric exercise itself in that iso-

metrically exercised muscles weredevoid of infiltrating cells, and thesame force decrement was not ob-served after isometric exercise of the

same duration. A similar scenariohas been proposed in human exer-cise studies.16

Because the inflammatory pro-cess itself can cause damage in ex-cess of that caused by the exercise, it

is possible that prevention of in-flammation would improve musclestatus following injury. Based onthis assumption, nonsteroidal anti-inflammatory drugs (NSAIDs) arecommonly prescribed to provideanalgesia and to improve perfor-mance. The specific objective effectsof the NSAIDs on muscle functionare, however, poorly understood,and it is difficult to test muscle func-tion in humans because the anal-

gesic effect of NSAIDs may itselfpermit improved performance bylessening or eliminating pain. Theanti-inflammatory medication flur-biprofen was tested in the rabbitmuscle injury model describedabove. Muscles were exercised witha single eccentric exercise session,after which the anti-inflammatorymedication was given for 7 days.17

Muscle contractile properties weremeasured for the 28 days following

the exercise; interestingly, musclestreated with the NSAID demon-strated a significant short-termimprovement in contractile function

Richa rd L. Lieber, PhD, a nd Jan Fridn , MD, PhD


Table 1Characteristics of Human Skeletal Muscle Fiber Types

Type I Type IIA Type IIB

Other names Red, slow twitch (ST) White, fast twitch (FT)Slow oxidative (SO) Fast oxidative glycolytic (FOG) Fast glycolytic (FG)

Speed of contraction Slow Fast FastFatigability Fatigue-resistant Moderately fatigue-resistant Most fatigableAerobic capacity High Medium LowAnaerobic capacity Low High HighMotor unit size Small Medium LargeCapillary density High Medium Low

(Adapted with permission from Garrett WE, Jr, Best TM: Anatomy, Physiology, and Mechanics of Skeletal Muscle, in Buckwalter JA,Einhorn TA, Simon SR [eds]: Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2. American Academy ofOrthopaedic Surgeons, Rosemont, Ill: 2000, p. 692.)


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but a subsequent loss in function(Fig. 5). These data may have sig-nificant implications for the use of

NSAIDs in pain treatment associatedwith neuromuscular injury.

Skeletal Muscle Pain

Numerous studies have documentedthe existence of pain after blunt trau-ma, eccentric exercise, injection ofnoxious agents, and peripheral nervedisease in skeletal muscles. It isclear, however, that muscle fiber

damage does not necessarily causepain. This statement is based on theobservation that muscle biopsies ob-tained from patients with primarymuscle diseases such as Duchennemuscular dystrophy reveal majordisruptions of the myofibrillar andsarcotubular apparatus, yet the pa-tients themselves remain pain free.Thus, pain within muscle that occursafter fiber injury probably resultsfrom secondary events that occur

after the damage itself. Based on thisevidence and extrapolation of experi-mental data obtained from muscles,

tendons, and joints, muscle pain isthought to result from stimulation ofnociceptors within the muscle itself.

Skele tal Muscle Inn ervation

Muscles are supplied by a richand extensive network of receptorsthat are innervated by small myelin-ated (group III) and unmyelinated(group IV) afferent nerve fibers.

These fibers conduct much moreslowly (Table 2) than do either the-motoneurons that project to themuscle fibers (i.e., extrafusal musclefibers), the -motoneurons that pro-ject to the muscle spindles (intra-fusal muscle fibers), or even the Iaafferents that feed back from musclespindles to the spinal cord.

Nociception in Skeletal Muscle

Although the bulk of the data on

the neurophysiology of pain hasbeen obtained from studies of cuta-neous receptors, studies of muscleand visceral pain are much moreclinically relevant. The extensivestudies by Mense et al18-20 provide awealth of understanding regardingthese nociceptive mechanisms inmuscle and viscera. They delineatedseveral important differences be-tween muscle and visceral paincompared with cutaneous pain.

First, cutaneous pain is localizedwith great accuracy, and musclepain is difficult to localize. Second,



A B

Figure 3 Longitudinal electron micrographs of rabbit tibialis anterior muscle after 30 min ofeccentric contractions. A, Sample from normal muscle showing clean alignment of myofi-

brils across the field. B, Sample from muscle showing smearing of the Z band material(small arrowheads) and extension of the Z bands into adjacent A bands (circled regions).

Figure 2 Cross-sectional light micrographs of rabbit tibialis anterior muscle under differentstaining conditions. Enlarged fiber, shown with arrows, is of the FG fiber type. A, Hema-toxylin-eosin. B, Myofibrillar adenosine triphosphate following preincubation at pH = 9.4.C, Succinate dehydrogenase. D, -Glycerophosphate dehydrogenase.

A B

C D

2 m


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while increasing the activation inten-sity of cutaneous receptors does notchange the size of the receptive field,increasing muscular pain intensityresults in referral to remote sites suchas other muscles, fascia, tendons,joints, or ligaments. Third, muscle

pain is associated with symptomsmediated through the autonomicnervous system, such as decreasedblood pressure, nausea, and sweat-ing, whereas cutaneous pain is not.

In contrast to results producedfrom analogous studies of the skin,repetitive electrical stimulation ofmuscle afferents results only inpainful sensations. Increasing the in-tensity does not modify the subjec-tive nature of the pain and serves

only to elicit the description of acramp as well as a decreased abilityto localize the site of pain source.21

Additionally, the magnitude of re-ferred pain is positively correlated tothe stimulation frequency of deepnociceptive fibers.

Factors That Modulate

Nociception in Skeletal Muscle

The type III and IV nociceptors inskeletal muscle have been studied

extensively in the cat hindlimb prep-aration.18,19 The percentages ofmotor and sensory nerves innervat-ing the lateral gastrocnemius-soleusmuscles have been shown to be ap-

proximately 60% and 40%, respec-tively. Of the sensory nerves, about40% of them can be classified asnociceptive, suggesting an overallhigh sensibility within these mus-cles (15% to 20% of the innervating

axons).Experimental demonstration of

factors affecting nociception is ob-tained by using single nociceptiveafferents from anesthetized catsand experimentally perturbing thesystem. For example, Mense andMeyer18 measured the dischargeactivity of these group III afferentsand saw almost no activity on lighttouch with a painters brush (Fig. 6),some activity on moderate touch,

and high activity with noxious touch(pinching the muscle with forceps).No activity was observed on pas-sive stretch of the muscle withinthe physiologic range (6 mm in thiscase), but when the muscle wasstretched 9 or 12 mm, a moderatelevel of activity was recorded. Thismakes teleologic sense becausenociceptors are designed not only



Figure 4 A, Cross-section of muscle fibers showing enlarged fiber (3) and two normalfibers (1 and 2), and muscle spindle (ms). B, Longitudinal section of muscle along planeshown in panel A (white dotted line) revealing the inflammatory process that leads to theenlarged fiber type (3) and size variation observed (compare with Fig. 2). Enlarged fibersthus represent supercontracted cells being digested by inflammatory cells close by.(Reproduced with permission from Fridn J, Lieber RL: Segmental muscle fiber lesionsafter repetitive eccentric contractions. Cell Tissue Res 1998;293:165-171.)

A B

2500

3000

2000

1500

1000

500Day 3 Day 7 Day 28

Days after Exercise

TAMaximumTension(g)

Untreated

Flurbiprofen

Figure 5 Maximum tetanic tension of tibialis anterior (TA) muscles from flurbiprofen-treated versus untreated animals. The flurbiprofen-treated animals generated higher mus-cle forces early in the treatment and lower muscle forces later in the treatment. (Adaptedwith permission.17)

1

2

3

1

2

3

ms

25 m


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to signal tissue damage but also toprevent it.

Inflammatory FactorsOther factors that caused in-

creased output from nociceptorswere injection of factors presumedto be involved in the inflammatoryresponse, such as bradykinin ([BK]cleaved from precursor plasma pro-teins), 5-hydroxytryptamine (re-leased from platelets after vasculardamage), and prostaglandins ([PGs]a byproduct of the cyclooxygenasepathway). All receptors studiedshowed clear signs of BK-inducedsensitization characterized by a low-

ered threshold to local pressurestimulation. Because BK is knownto release PGE2 from cells, it canactually potentiate its own action.This finding has led to the idea thatcompounds that block the effect ofPG synthesis (e.g., acetylsalicylicacid [ASA]) might reduce or abolishthe stimulatory action of BK. Thiswas, in fact, the case. There was acomplete lack of effect of BK within15 minutes of injection of ASA,

demonstrating the peripheral effectof ASA in that connections with thecentral nervous system were cut inthis preparation.

IschemiaIschemia for prolonged periods

(up to about 15 minutes) is notpainful and does not evoke sympa-thetic reflexes. However, if a musclecontracts under ischemic conditions,pain rapidly develops. Most likely

BK is involved in this response be-cause kinin is released from plasmaproteins during ischemia. Menseand Stahnke19 demonstrated activa-tion of group IV muscle receptors

during ischemic contractions. Mus-cle contraction alone did not elicitthe response, but afferent activity in-creased fourfold when the same con-traction was performed while oc-cluding the nutrient artery.

Reflex-Mediated PainReports in some of the older clin-

ical literature suggest that increasedactivity or excitability of the -motorsystem causes the painful spasms

that sometimes appear in skeletalmuscle. Increased activity of the -motor system would then lead toincreased discharge frequency inmuscle spindle afferent fibers that

would, in turn, lead to increasedactivation of-motoneurons. Bythis mechanism, a vicious cyclecould result that would be strongenough to lead to ischemic contrac-tions and pain by any one of a num-

ber of the mechanisms describedabove. Unfortunately, experimentalevidence supporting this concept islacking.20 The main finding of thesestudies was that resting activity ofthe -motoneurons was significantlyreduced by inflammation and thatthe reflex excitability of the neuronswas likewise inhibited. These re-sults demonstrated that nociceptivemuscle afferents actually inhibithomonymous -motoneurons, which

may represent an advantage to themuscle in that it could reduce po-tentially damaging forces on it.

Summary

DOMS represents a time-varyingcascade of events that are uniquelyassociated with eccentric training ofa skeletal muscle. Currently, thereis not an adequate explanation for

the relationship between muscledamage observed and clinical symp-toms of pain. Intramuscular pain,similar to that observed after appli-cation of inflammatory factors to



60 s

Thermosensitive unit (group IV)

Touch Mod.

p.

Nox.

p.3 6 9 12 2 4 6

Stretch (mm) Contraction (kP)

Force 500

0

Counts (2s)110

5

0Impulses(2s

)1

Figure 6 Recording from intramuscular type III afferents with pressure of different levels(left portion of panel) and with stretch above and beyond the physiological range (6 mm inthis case). (Reproduced with permission.18)

Table 2Properties of Afferent Fibers in Peripheral Nerve

Axon AverageFiber Group Myelinated Diameter (m) Conduction (m/s)

I Yes 15 90-100II Yes 10 40-50III Yes 5 20-30IV No


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muscle, is likely to account for someof the DOMS observed. In addition,it is possible that reflex-mediatedpain also contributes to DOMS. In

the future, investigators will estab-lish objective human models forDOMS and perform more sophisti-cated neurophysiologic analysis and

noninvasive imaging of the neuro-muscular system to define the mech-anism and prevention of DOMSafter athletic endeavors.



References

1. Howell JN, Chleboun G, Conatser R:Muscle stiffness, strength loss, swellingand soreness following exercise-induced injury in humans. J Physiol1993;464:183-196.

2. Fridn J: Muscle soreness after exer-cise: Implications of morphologicalchanges. Int J Sports Med 1984;5:57-66.

3. Ebbeling CB, Clarkson PM: Exercise-induced muscle damage and adapta-tion. Sports Med 1989;7:207-234.

4. Newham DJ, Mills KR, Quigley BM,Edwards RH: Pain and fatigue afterconcentric and eccentric muscle con-tractions. Clin Sci (Lond) 1983;64:55-62.

5. Evans WJ, Meredith CN, Cannon JG, etal: Metabolic changes following eccen-tric exercise in trained and untrainedmen. J Appl Physiol 1986;61:1864-1868.

6. Asmussen E: Observations on experi-mental muscular soreness. Acta RheumScand 1956;2:109-116.

7. Lieber RL, Fridn J: Muscle damage isnot a function of muscle force but activemuscle strain. J Appl Physio l1993;74:520-526.

8. Warren GL, Hayes DA, Lowe DA,Armstrong RB: Mechanical factors inthe initiation of eccentric contraction-induced injury in rat soleus muscle. J

Physiol 1993;464:457-475.9. Lieber RL, Thornell LE, Fridn J: Muscle

cytoskeletal disruption occurs within thefirst 15 minutes of cyclic eccentric con-traction. J Appl Physiol 1996;80:278-284.

10. Nimmo MA, Snow DH: Time courseof ultrastructural changes in skeletalmuscle after two types of exercise. JAppl Physiol 1982;52:910-913.

11. Warhol MJ, Siegel AJ, Evans WJ, Silver-man LM: Skeletal muscle injury and

repair in marathon runners after com-petition. Am J Pathol 1985;118:331-339.12. Lieber RL, Fridn J: Selective damage

of fast glycolytic muscle fibres witheccentric contraction of the rabbit tib-ialis anterior. Acta Physiol Scand 1988;133:587-588.

13. Fridn J: Changes in human skeletalmuscle induced by long-term eccentricexercise. Cell Tissue Res 1984;236:365-372.

14. Patel TJ, Cuizon D, Mathieu-CostelloO, Fridn J, Lieber RL: Increasedoxidative capacity does not protectskeletal muscle fibers from eccentriccontraction-induced injury. Am J

Physiol 1998;274(5 pt 2):R1300-R1308.15. Armstrong RB, Ogilvie RW, Schwane

JA: Eccentric exercise-induced injuryto rat skeletal muscle. J Appl Physiol

1983;54:80-93.16. Cannon JG, Orencole SF, Fielding RA, et

al: Acute phase response in exercise:Interaction of age and vitamin E on neu-trophils and muscle enzyme release. Am

J Physiol 1990;259(6 pt 2):R1214-R1219.17. Mishra DK, Fridn J, Schmitz MC,

Lieber RL: Anti-inflammatory med-ication after muscle injury: A treat-ment resulting in short-term improve-ment but subsequent loss of muscle

function. J Bone Joint Surg Am 1995;77:1510-1519.18. Mense S, Meyer H: Different types of

slowly conducting afferent units in catskeletal muscle and tendon. J Physiol1985;363:403-417.

19. Mense S, Stahnke M: Responses inmuscle afferent fibres of slow conduc-tion velocity to contractions and isch-aemia in the cat. J Physiol 1983;342:383-397.

20. Mense S, Skeppar P: Discharge behav-iour of feline gamma-motoneuronesfollowing induction of an artificialmyositis. Pain 1991;46:201-210.

21. Torebjrk HE, Ochoa JL, Schady W:Referred pain from intraneural stimu-lation of muscle fascicles in the medi-an nerve. Pain 1984;18:145-156.
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Lieber Jaaos 2002