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At stumps on the second day, Sri Lanka had collapsed to 91 for six, still a huge 460 behind England's first innings 551 for six declared and needing a further 261 to avoid the follow-on target of 352.
Mahmood, the 24-year-old Lancashire fast bowler, took three wickets for no runs in nine balls to end the day with figures of 5-2-9-3.
Sri Lanka captain Mahela Jayawardene, dropped by diving wicket-keeper Geraint Jones on 34, was 40 not out and Farveez Maharoof unbeaten on six at stumps.
Earlier, Kevin Pietersen scored 158 to equal his Test-best score in what was England's highest total against Sri Lanka, a stand of 173 with Paul Collingwood (57) the centrepiece of the innings.
After Matthew Hoggard had struck a couple of early blows, Mahmood - the cousin of British boxing star Amir Khan - delivered some knockout punches of his own, breaking the 90mph barrier and bowling with a venom way beyond anything the Sri Lankan quicks had managed.
The way the touring side's reply began suggested Sanath Jayasuriya, the former captain, could not arrive in England quickly enough after the veteran left-handed opener recently announced he was ending his Test retirement.
Jehan Mubarak had been drafted in as an opener after Michael Vandort had made a pair in last week's 10-wicket defeat by England A. However, Mubarak fell for nought, lbw to Hoggard's inswinging seventh ball as Sri Lanka lost their first wicket without a run on the board. Upul Tharanga, the fellow left-hand opener, exited in similar fashion for ten, his dismissal made worse by the fact he was shouldering arms. Hoggard had taken two wickets for seven runs in 18 balls to take his Test tally to 199.
Kumar Sangakkara and Jayawardene, the most experienced batsmen, staunched the flow of wickets with a stand of 60. But Sangakkara went for 20 when, driving loosely outside off-stump against Mahmood, he was caught by Marcus Trescothick at first slip to give the bowler his first Test wicket with only his 12th ball.
Mahmood then had Thilan Samaraweera plumb lbw for none before Tillakaratne Dilshan also went for nought after he was run-out having been sent back by Jayawardene. And when debutant Chamara Kapugedera then fell for a first-ball nought, also lbw to Mahmood, Sri Lanka had lost four wickets for four runs in 21 balls.
Earlier Pietersen's hundred was his third Test century and his first at Lord's as England surpassed their previous best against Sri Lanka of 545 at Edgbaston in 2002. Muttiah Muralitharan was one of three bowlers who conceded more than 100 runs, taking three for 158 in 48 overs in what was the off-spinner's first Test at Lord's.
Pietersen, who batted for five fours, equalled his Ashes-clinching 158 at The Oval in September by clipping Chaminda Vaas for four. But next ball he was lbw to the left-arm quick. Pietersen faced 205 balls with two sixes and 19 fours having been caught off a Maharoof no-ball for 52 on Thursday.
Andrew Flintoff (33 not out) lofted his former Lancashire team-mate Muralitharan for six before repeating the dose and then declaring as he continued to deputise as captain for Michael Vaughan.
England, who won the toss in the first of a three-match series, started Friday on 318 for three after opener Marcus Trescothick had made 106 and Alastair Cook, in his first Test in England, 89.
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