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Mickelson fired a four-under 66
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America's Phil Mickelson and Australia's Rod Pampling lead the USPGA at four under par after the first round at the Oak Hill Country Club in Rochester, New York.
The pair made the most of their early starts to card 66s before the heat and humidity increased.
They lead by one from American Billy Andrade on the tough par-70 course.
One shot further back were Masters champion Mike Weir and twice US Open champion Lee Janzen, with a logjam of players on one under including Fiji's Vijay Singh and young Australian Aaron Baddeley.
World number one Tiger Woods struggled with his game, especially off the tee, and lurched to a four-over 74, while South Africa's Ernie Els fired just one birdie in a 71.
US Open champion Jim Furyk hit a 72 and
Open winner Ben Curtis carded a 75, while holder Rich Beem slumped to a disastrous 12-over 82, as did Scotland's Colin Montgomerie.
The best of the Europeans were Ireland's Padraig Harrington, England's Ian Poulter and Spain's Sergio Garcia, who all ended at two over.
But Ulsterman Darren Clarke and England's Paul Casey also found going tough with a 79.
Left-hander Mickelson, chasing his first major win in 46 starts, began from the 10th and picked up three birdies in his first four holes.
He dropped a shot at the 17th but immediately made amends to go out in 32.
Further birdies at the second and fourth took him to five under but he left a par putt inches short on the last to drop back alongside Pampling.
The 33-year-old from Queensland picked up two birdies in either half on his USPGA debut.
Two-times champion Woods, who is chasing his ninth major and first of the year, picked up only one birdie and dropped five shots.
In-form Kenny Perry, who has won three times in his
last seven PGA Tour starts, signed for a 75.
Australia's Robert Allenby hit a hole-in-one with a four iron at the 226-yard par-three 11th hole. It was the 32nd ace at the USPGA since 1975 but he went on to finish level par.